Show Summary Details
Page of

Disorders of peroxisomal metabolism in adults 

Disorders of peroxisomal metabolism in adults
Chapter:
Disorders of peroxisomal metabolism in adults
Author(s):

Anthony S. Wierzbicki

DOI:
10.1093/med/9780199204854.003.1209_update_002

July 30, 2015: This chapter has been re-evaluated and remains up-to-date. No changes have been necessary.

Update:

Data on biochemistry of peroxisomal enzymes and transporters updated.

Mechanism of toxicity of phytanic and pristanic acids updated.

Description of the adult presentation of acyl-coenzymeA oxidase deficiency as the cause of pseudoadrenoleukodystrophy.

Data on the pathophysiological mechanisms behind adrenoleukodystrophy updated.

Updated on 28 Nov 2013. The previous version of this content can be found here.
Page of

PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford University Press, 2015. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use (for details see Privacy Policy).

Subscriber: null; date: 11 December 2017

Essentials

The peroxisome is a specialized organelle which employs molecular oxygen in the oxidation of complex organic molecules including lipids. Enzymatic pathways for the metabolism of fatty acids, including very long-chain fatty acids (VLCFA) enable this organelle to carry out β‎-oxidation in partnership with mitochondria. A peroxisomal pathway for isoprenoid lipids derived from chlorophyll, such as phytanic acid, utilizes α‎-oxidation, but a default mechanism involving ω‎-oxidation may also metabolize phytanic acid and its derivatives.

The biochemical manifestations, molecular pathology, and diverse clinical features of many peroxisomal disorders have now been clarified, offering the promise of prompt diagnosis, better management and useful means to provide appropriate genetic counselling for affected families. At the same time, specific treatments including rigorous dietary interventions and plasmapheresis to remove undegraded toxic metabolites offer credible hope of improvement and prevention of disease in affected individuals.

Inborn errors of peroxisomal metabolism usually present in infancy and childhood, but some disorders typically become manifest later in life and in adults, in whom the progress is often slow.

Particular adult peroxisomal disorders

X-linked adrenoleukodystrophy (X-ALD)—due to mutation in the gene for an ATP-binding cassette (ABC) protein of unknown function and characterized by accumulation of unbranched saturated VLCFAs, particularly hexacosanoate (C26), in the cholesterol esters of brain white matter, adrenal cortex and certain sphingolipids of the brain. The disease has multiple phenotypes: it may present in adolescence with slowly progressive stiffness, clumsiness, weakness, weight loss, and skin pigmentation typical of Addison’s disease; it may present in adults with primarily psychiatric manifestations. Most cases develop increasing handicap; management is palliative and supportive in most instances.

Adult Refsum’s disease—due in most cases to mutation in the gene for phytanoyl CoA-hydroxylase (PhyH) such that patients are unable to detoxify phytanic acid by α‎-oxidation and have greatly elevated levels of this in their plasma. Usually presents in late childhood with progressive deterioration of night vision, the occurrence of progressive retinitis pigmentosa, and anosmia; late features include deafness, ataxia, polyneuropathy, ichthyosis and cardiac arrhythmias. Treatment is by restriction of dietary phytanic acid, with or without its elimination by plasmapheresis or apheresis.

Neuropsychiatric adult peroxisomal disorders

Historical perspective

The likely first description of X-linked adrenoleukodystrophy (X-ALD; OMIM 300100) was in 1910 when a 6-year-old child developed abnormal eye movements, apathy, and mental deterioration. His gait then deteriorated and skin darkening was noted prior to his death a few months later. Examination of the brain by Schilder showed central demyelination, perivascular lymphocytes, foam cells, and gliosis which he termed encephalitis periaxalis diffusa. Other cases he later described are likely due to other leukodystrophies. Adrenoleukodystrophy was defined in 1970, with its characteristic adrenal changes of excess very long chain fatty acids (VLCFAs) and cholesterol esters present in cell inclusion bodies. These VLCFAs were later identified as pathognomic and identifiable in plasma samples and the primary defect was identified as an inability to metabolize them. The gene was mapped to Xq18 and identified as a member of the ATP-binding cassette (ABC) transporter family. X-ALD was localized to the peroxisome. Subsequently, mouse models have been developed which show similar clinical features to human disease.

Aetiology

Adrenoleukodystrophy is characterized by the accumulation of unbranched saturated VLCFAs with a chain length of 24 to 30 carbons, particularly hexacosanoate (C26), in the cholesterol esters of brain white matter, in the adrenal cortex, and in certain sphingolipids of the brain. The disorder shows X-linked inheritance with expression in female heterozygotes. The disruptive effects of the accumulation of VLCFAs, especially hexacosanoic acid (C26:0), on cell membrane structure and function may explain the neurological manifestations seen in adrenoleukodystrophy patients. VLCFAs cause alterations in membrane fluidity and affect cortisol secretion from cultured cells of adrenal cortical origin. In addition, albumin has only one C26 binding site compared with more than six for shorter fatty acids, so limiting its efficacy as a reverse transport protein for excess VLCFAs.

Clinical features

X-ALD is heterogeneous. Seven phenotypes occur in males and five are recognized in females (see Table 12.9.1). Childhood cerebral adrenoleukodystrophy presents between the ages of 5 and 10 years with emotional lability, hyperactivity/withdrawal, and mental deterioration, mimicking attention deficit disorder which evolves to parietal lobe dysfunction with apraxia, astereognosis, and later dementia. MRI shows a characteristic pattern of symmetric involvement of the posterior parieto-occipital white matter in 85% of patients, frontal involvement in 10%, and an asymmetric pattern in the rest.

Table 12.9.1 Psychiatric signs and inborn errors of metabolism in adolescents and adults

Disorder

Confusion

Mental retardation

Behavioural disturbance

Catatonia

Visual hallucination

Psychosis

Depression

Urea cycle defect

+

+/–

+

+

+

+

+

Homocysteine disorders

+

+

+

+

+

+/–

+

Porphyria

+

+

+

+/–

+/–

Wilson’s disease

+/–

+

+/–

+

CTX

+

+

+

+

MLD

+

+

GM2 gangliosidosis

+

+

+

+

+

Mannosidoses

+

+

+

+

+

X-ALD

+

+

+

Acyl-coenzymeA oxidase (pseudoneonatal adrenoleukodystrophy)

+

+

+

Nonketotic hyperglycinemia

+

+

Monoamine oxidase A deficiency

+

+

Creatine transporter deficiency

+

+

Succinic semi-aldehyde dehydrogenase deficiency

+

+

Niemann–Pick C

+

+

+

+

+

CTX, cerebrotendinous xanthomatosis; MLD, metachromatic leukodystrophy; X-ALD, X-linked adrenoleukodystrophy.

Reproduced from Sedel F et al. (2007a). Psychiatric manifestations revealing inborn errors of metabolism in adolescents and adults. J Inherit Metab Dis, 30, 631–41, with permission.

The adolescent form is adenomyeloneuropathy which presents with slowly progressive stiffness, clumsiness, weakness, weight loss, and skin pigmentation typical of Addison’s disease. Autonomic function including micturition and erectile function are affected later. Somatosensory, auditory, and brainstem evoked potential are abnormal with some cases of abnormal visual and peripheral nerve conduction abnormalities. Brain MRI scans are abnormal in 50% of men and 80% of women, usually affecting corticospinal tracts with later parenchymal changes. Depression and emotional lability are common. Adult cerebral adrenoleukodystrophy is a variant of adenomyeloneuropathy occurring after age 20 without spinal cord symptoms. The primary signs are psychiatric with a presentation of psychotic mania and may include schizophrenia or dementia.

Some cases show a pure initial addisonian picture with no neurological involvement; all are autoantibody negative. The onset of Addison’s disease is usually in childhood but the neurological changes follow in 20 to 30 years. Subtle hyperreflexia or impaired vibration sense and subtle MRI or neurophysiological signs may be detected earlier in these cases.

In female adrenoleukodystrophy heterozygotes, adrenal cortical insufficiency rarely develops, although isolated mineralocorticoid insufficiency may occur but may be difficult to diagnose. Furthermore, adrenoleukodystrophy heterozygotes are predisposed to hypoaldosteronism related to the use of nonsteroidal anti-inflammatory agents (NSAIDs). A subclinical decrease in glucocorticoid reserve, as measured by synthetic ovine corticotropin-releasing hormone testing, may be present in most of these women. Aldosterone levels should be included in ACTH stimulation testing done to detect adrenal insufficiency in affected women. NSAIDs should be considered a risk factor for the development of hypoaldosteronism in women who are heterozygous for adrenoleukodystrophy.

Rare presentations include olivopontocerebellar atrophy which has been described as X-ALD ataxia in Japanese. Other uncommon presentations include unilateral masses which can mimic brain tumours and cases of spontaneous remission of neurological symptoms.

Women who are X-ALD heterozygotes usually present with adenomyeloneuropathy at age 30 to 40. Subtle signs are often detected prior to presentation but eventually the full picture occurs, with late-onset dementia.

A clinical syndrome that mimic features of ALD is acyl-coenzymeA oxidase deficiency but most cases present with severe neonatal disease.

Neuropathology

There are two distinct forms of neuropathology associated with X-ALD. Pure adrenomyeloneuropathy is a distal axonic neuropathy while the cerebral forms are associated with inflammation. In cerebral X-ALD, brain pathology is often grossly normal though with signs of cerebral atherosclerosis. Grey matter is unaffected but white matter disease occurs in a rostrocaudal direction with demyelination prominent in the parieto-occipital cortex and the cerebellum. The detailed pathology shows oligodendroglial cell loss, astrocytosis, and a perivascular inflammatory infiltrate. In the noncerebral form, demyelination is seen in the corticospinal tracts with no obvious inflammation and only mild gliosis and occasional macrophages. In the adrenal cortex, cells are filled with lamellar deposits of cholesterol esters with primary cortical atrophy and no evidence of inflammation or antibodies, with milder changes in the adrenomyeloneuropathy form. In men with X-ALD, the testes show Leydig cell alterations, again with lamellar deposits. It has been estimated that at least 10% of males with Addison’s disease (adrenocortical failure) have X-linked adrenomyeloneuropathy or unrecognized X-ALD.

Metabolism of VLCFAs

VLCFAs are derived from the diet and endogenous synthesis with between 20 and 80% derived from synthesis, depending on the study. The synthetic pathway occurs in brain microsomes with repeated additions of malonyl-CoA units to palmitic (C16:0) or stearic (C18:0) acid precursors. There are probably separate pathways for C20: 0 and C22:0 (behenic) fatty acids with the C22:0 pathway also elongating C22:1 (erucic) acid. Degradation of VLCFAs occurs by β‎-oxidation within peroxisomes after activation by specific acyl-CoA ligases which are chain length specific, so that a very long chain-CoA synthetase exists. In actuality, there are multiple very long chain-CoA synthetases with differing tissue and organelle specificities, all of which contain AMP-binding domains and a long chain synthetase domain. Both very long chain-CoA synthetases and microsomal fatty acid transfer protein-1 have very long chain-CoA synthetase activity but may function differently in the synthesis and degradation of VLCFAs.

The X-ALD protein and its homologues

The X-ALD gene was mapped to a region of the X-chromosome close to the glucose-6-phosphate dehydrogenase gene. The gene was established to code for an ABC protein of still unknown function but likely to involve the translocation of a variety of substrates across extra and intracellular membranes, including lipids, sterols, and drugs. The ABCD1 protein (adrenoleukodystrophy protein) maps to Xq28 and is mutated in X-ALD.

ABCD1 is a member of the ABC transporter superfamily. It expresses a half transporter which is located in the peroxisome. The gene has an open reading frame of 2235 bases which encodes a 745-amino acid protein with 38.5% amino acid identity and 78.9% similarity to another peroxisomal protein (ABCD3).

Mutations in ABCD1 result in X-ALD in animal models, with elevated VLCFAs. ABCD1 is one of four related peroxisomal transporters that are found in the human genome, the others being ABCD2 (adrenoleukodystrophy related protein) (OMIM 601081), ABCD3 (peroxisomal membrane protein 70) (OMIM 170995), and ABCD4 (P70R/PMP69) (OMIM 603214). The adrenoleukodystrophy protein and the adrenoleukodystrophy-related protein are expressed on oligodendroglia, while the adrenoleukodystrophy-related protein and peroxisomal membrane protein 70 are found in neurons of the central nervous system. These genes are highly conserved in evolution, and two homologous genes are present in the yeast genome, PXA1 and PXA2, which also transport long chain fatty acids. The 80-kDa protein encoded by this gene is absent in patients with X-ALD, in whom X-ALD mRNA was undetectable. Most of the ABCD1 mutations (>450) in X-ALD are point mutations, but large deletions have been described. There is no correlation between genotype and phenotype. In 15 to 20% of obligate female heterozygotes, false-negative results occur for plasma VLCFAs. Mutation analysis is the only reliable method for the identification of heterozygotes.

Overexpression of the adrenoleukodystrophy protein and its homologue, the adrenoleukodystrophy-related protein (ABCD2), can restore the impaired peroxisomal β‎-oxidation in the fibroblasts of adrenoleukodystrophy patients. However, it seems that functional replacement of the adrenoleukodystrophy protein by adrenoleukodystrophy-related protein is not due to stabilization of the mutated adrenoleukodystrophy protein. Similarly, the adrenoleukodystrophy-related protein and peroxisomal membrane protein 70 could restore the peroxisomal β‎-oxidation defect in the liver of adrenoleukodystrophy protein-deficient mice by stimulating Aldr and Pmp70 gene expression through a dietary treatment with the peroxisome proliferator fenofibrate. These results suggested that a correction of the biochemical defect in adrenoleukodystrophy might be possible by drug-induced overexpression or ectopic expression of the adrenoleukodystrophy-related gene. The adrenoleukodystrophy protein transporter may facilitate the interaction between peroxisomes and mitochondria, the two sites within the cells where β‎-oxidation of VLCFAs occurs. The phenotype of x-ALD was thought to be based on microglial activation for cerebral effects, while inflammation is less involved in AMN but transcriptome studies show that a combination of effects of the deficiency on oxidative phosphorylation, adipocytokine and insulin signalling are responsible for the phenotypes.

Epidemiology

Screening and diagnostic records suggest that the prevalence is a minimum of 1 in 22 500 to 62 000. In contrast, the use of the Hardy–Weinberg approach and genetic frequency data suggests a combined male to female frequency of 1 in 18 000 similar to phenylketonuria (1 in 12 000).

Differential diagnosis

The differential diagnosis of neuropsychiatric abnormalities is shown in Table 12.9.2. X-ALD can mimic attention deficit disorder, multiple sclerosis, organic dementias, and psychoses among neurological diseases and Addison’s disease and hypogonadism among endocrine disorders (see Table 12.9.2). The critical clinical differential element is the finding of abnormal ACTH levels and skin pigmentation with neurological signs, however subtle.

Table 12.9.2 Differential diagnosis of X-ALD

Presentation

Differential diagnosis

Childhood neurological with normal endocrinology

Hyperactivity; attention deficit disorder

Epilepsy/seizures

Brain tumour

Metachromatic/globoid leukodystrophy

Postencephalitic syndromes,: e.g. subacute sclerosing panencephalitis

Myelinoclastic diffuse sclerosis

Childhood neurological with hypoadrenalism

Addison’s disease with posthypoglycaemic damage

X-linked glycerol kinase deficiency

Central pontine myelinolysis

Glucocorticoid deficiency with achalasia

Hypoadrenalism

Secondary causes of hypoadrenalism

Adrenomyeloneuropathy

Multiple sclerosis

Familial or other spastic parapereses

Spinocerebellar/olivopontocerebellar degeneration

Cervical spondylosis

Spinal cord tumour, e.g. ependymoma

Adult cerebral

Schizophrenia

Depression

Epilepsy/ organic psychosis

Alzheimer’s disease or other dementias

Brain tumour

Heterozygote with symptoms

Multiple sclerosis

Chronic spinal disease

Spinal cord tumour

Cervical spondylosis

Clinical investigation

Clinical biochemistry

The primary abnormality in X-ALD is an accumulation of VLCFAs (>C22) which occur in myelin. C26:0 can account for up to 5% of brain cerebrosides and sulphatides. In X-ALD, both saturated and unsaturated forms of C26:0 (cerotic) and C24:0 (lignoceric) acids accumulate with reductions in C24:1(n – 9) (nervonic) acid. Normally shorter fatty acids accumulate in brain cholesterol esters, but in X-ALD, by contrast, these are mostly C26:0 and are enriched in myelin and in areas of demyelination. Similarly, C26:0 accumulates in white matter phosphatidylcholine phospholipids, C24:0 and C24:1 in gangliosides. Erythrocytes, plasma, and cultured fibroblasts all contain a 2 to 10-fold excess of VLCFAs. The diagnostic test relies on measurement of C26:0 levels and the ratios of C26 to C22:0 (docosahexaenoic acid) and C26:0 to C24:0 (tetracosanoic acid).

Results can be confirmed by fibroblast studies or by the use of sequencing techniques. Highly elevated VLCFA levels are also found in peroxisomal biogenesis disorders but these show a different clinical presentation to X-ALD or transiently with ketogenic diets for seizures. False negative results may occur in patients consuming excess C22:1; ω‎ – 9 (erucic acid; Lorenzo’s oil) which is found in mustard and rapeseed oils. A few affected males (0.1%) have borderline normal C26:0 levels and 15% of obligate female carriers have normal results. Effective mutation detection in these families is therefore fundamental to the unambiguous determination of genetic status. Of particular concern are female members of kinships with segregating X-ALD mutations, because normal levels of VLCFA do not guarantee a lack of carrier status. Prenatal diagnosis is possible from cultured amniocytes or chorionic villus cells. Abnormal liver function tests are a common finding in adrenoluekodystrophies and occur secondary to disturbances in di- and trihydroxy-cholestanoic acid (DHCA and THCA) metabolism.

Radiology

An MRI scan often reveals biochemical changes before the development of clinical symptoms. Eighty per cent of childhood cerebral adrenoleukodystrophy patients have symmetric periventricular white matter changes in the posterior parietal and occipital lobes with a dorsocaudal progression with time. Contrast studies show up areas of active demyelination, inflammation with breakdown of the blood–brain barrier and gliosis. Proton spectroscopy using N-acetyl aspartate shows up neuronal loss, while choline compound studies assaying phosphocholine and glycerophosphocholine indicate membrane turnover and demyelination, and myo-inositol compounds seem to be indices of gliosis. The presence of lactate indicates the anaerobic metabolism of the inflammatory cell infiltrate. In the adrenomyeloneuropathy brain, MRIs may be normal in 50% of men and 80% of women but diffuse spinal cord atrophy is present.

Endocrinology

Overt hypoadrenalism occurs in 40% of patients with childhood cerebral adrenoleukodystrophy and 80% have a deficient cortisol response on Synacthen testing. In childhood disease 80% show abnormal adrenal stimulation test results, while in adrenomyeloneuropathy between 30% and 50% show normal responses. Clinical Addison’s disease is found in 1% of female heterozygotes. In adrenoleukodystrophy heterozygotes, adrenal cortical insufficiency rarely develops, although hypoaldosteronism may occur, especially if NSAIDs are being used. ACTH levels are increased in male patients. Levels of follicle-stimulating hormone (FSH) or luteinizing hormone (LH) are increased in 50% to 70% of patients with adrenomyeloneuropathy, while testosterone levels are reduced in 20% with low normal levels of dehydroepiandrosterone sulphate.

Neurophysiology

Hearing is normal but brainstem auditory evoked potentials are abnormal in 95% of adrenomyeloneuropathy patients and 42% of heterozygote patients. Abnormalities in visual evoked potentials are also found as latencies and are increased in 20% of men with adrenomyeloneuropathy but in more than 70% with childhood cerebral disease. Electroretinograms are normal. Subtle demyelination and axonal loss patterns of nerve conduction are found in 90% of men and 67% of women with adrenomyeloneuropathy, usually affecting the legs more than the arms. Neuropsychological tests can show up deficits in parieto-occipital function affecting visuospatial parameters and auditory processing, while frontal lobe lesions affect executive functions, emotions, problem solving, and anticipatory processing.

Treatment

The progressive nature of X-ALD means that comprehensive family and professional management support services are required. Leukodystrophies are associated with progressive learning difficulties, psychiatric disturbance, and increasing disability. Painful muscle spasms are common and should be managed with diazepam, baclofen, or gabapentin. Bulbar muscle function may be lost with disease progression, thus requiring special attention to feeding to reduce the risk of aspiration pneumonia.

Dietary therapy was based on the restriction of the intake of C26:0 to less than 15% of normal intake, but early trials showed no effect of this on levels of VLCFA levels. Addition of oleic acid normalized VLCFA levels in fibroblasts and oral glyceryl trioleate reduced VLCFA levels by 50% with an improvement in nerve conduction measures. A 4:1 combination of glyceryl trioleate and trierucate (Lorenzo’s oil) normalized VLCFA levels within 1 month and prompted mass use of this intervention. No evidence of a clinically relevant benefit from dietary treatment with Lorenzo’s oil has been seen in many studies of patients with neurological involvement and X-ALD, and asymptomatic thrombocytopenia was noted in 30% of patients. The fatty acid composition of the plasma and liver, but not that of the brain, improves with this therapy, suggesting that little erucic acid crossed the blood–brain barrier. Thus, dietary supplementation with Lorenzo’s oil is of limited value in correcting the accumulation of saturated VLCFAs in the brain of patients with established neurological adrenoleukodystrophy.

In a study of 89 asymptomatic boys with X-ALD who had normal MRI scans, Lorenzo’s oil and moderate fat restriction were prescribed for 6.9±2.7 years. Plasma fatty acids and clinical status were followed as measures of outcome. Twenty-four per cent developed MRI abnormalities and 11% developed neurological and MRI abnormalities. The trial concluded that the reduction of C26:0 by Lorenzo’s oil was associated with a reduced risk of developing MRI abnormalities. Lorenzo’s oil therapy is indicated in asymptomatic boys with X-ALD who have normal brain MRI scans. Experience with other adrenoleukodystrophy patients indicated that total fat intake in excess of 30 to 35% of total calories may counteract or nullify the C26:0-reducing effect of Lorenzo’s oil.

Patients who develop progressive MRI abnormalities should be considered for haematopoietic stem cell transplantation, but the 5-year mortality is 38% and survival is increased by 8 months on average. Results in 283 boys with X-ALD who received haematopoietic cell bone marrow transplantation showed that the estimated 5-year survival was 66%. The leading cause of death was disease progression. Donor-derived engraftment occurred in 86% of patients. Demyelination involved parietal–occipital lobes in 90%, leading to visual and auditory processing deficits in many boys. Bone marrow transplantation must be considered very early, even in a child without symptoms but with signs of demyelination on MRI, if a suitable donor is available. There are few data on the usefulness of bone marrow transplantation in adrenomyeloneuropathy.

Adrenal function must be monitored since 80% of asymptomatic patients with adrenoleukodystrophy develop evidence of adrenal insufficiency and adrenal hormone replacement therapy should be provided when indicated by laboratory findings.

Given the inflammation associated with X-ALD, a number of immunosuppressive regimes have been investigated. Studies of cyclophosphamide, immunoglobulin, and interferon-β‎ have been unsuccessful.

Prognosis

The prognosis in X-ALD depends on the presentation. As yet, there are no methods of determining which type of disease will result from a given mutation as genotype–phenotype correlation is poor. Once leukodystrophy begins, the prognosis is poor as progression is inevitable.

Future developments

Other potential therapeutic approaches to X-ALD include the use of lipid-lowering drugs. Lowering cholesterol activates human ABCD2 in cultured cells. In mice, a sterol regulatory element exists in the ABCD2 promoter and overlaps sites for liver X receptor/retinoid X receptor heterodimers. Adipose ABCD2 is induced by SREBP1c, whereas hepatic ABCD2 expression is down-regulated by concurrent activation of liver X receptor-α‎ and SREBP1c. Hepatic ABCD2 expression in liver X receptor-α‎/β‎ mice is inducible to levels vastly exceeding wild type.

Statins (3-HMG-CoA reductase inhibitors) are capable of normalizing VLCFA levels in primary skin fibroblasts derived from X-ALD patients. They block the induction of proinflammatory cytokines through effects on rho kinase. Twelve patients with X-ALD were treated with lovastatin for up to 12 months. Levels of C26:0 declined from pretreatment values and stabilized at various levels during a period of observation of up to 12 months, which does not correlate with the type of adrenoleukodystrophy gene mutation. In six patients, erythrocyte C26:0 levels fell by 50%. All patients with adrenomyeloneuropathy remained neurologically stable. However, follow-up trials have been unsuccessful.

The PPAR-α‎ agonist-mediated induction of ABCD2 expression seems to be indirect and possibly mediated by the sterol-responsive element-binding protein 2 in mice, but there are no published human studies of fibrate therapy. Sodium 4-phenylbutyrate reduces VLCFA levels through its effects on peroxisomal function and increases adrenoleukodystrophy-related protein levels. However human studies have failed to show consistent beneficial effects. Studies on potential pharmacological interventions on VLCFA metabolism have shown that in human fibroblast studies the pan-peroxisomal proliferator activating receptor (PPAR) agonist bezafibrate reduced VLCFA levels by inhibiting synthesis rather through than any effect on PPAR activity or β‎-oxidation.

Omega oxidation is an alternative oxidation route for VLCFAs. These fatty acids are substrates for the ω‎-oxidation system in human liver microsomes and are converted into ω‎-hydroxy fatty acids and further oxidized to dicarboxylic acids via cytochrome P450-mediated reactions. The high sensitivity towards the specific P450 inhibitor 17-octadecynoic acid suggested that ω‎-hydroxylation of VLCFAs is catalysed by the CYP4A/F subfamilies, particularly CYP4F2 and CYP4F3B, and that therapies capable of increasing ω‎-oxidation may have the potential to reduce the progression of the disease. Recently gene therapy has been attempted for X-ALD using lentivirus transformation of white cells and 9-14% of cells showed reconstitution of ABC-D1 expression over 24 months.

Neuro-ophthalmic adult peroxisomal disorders

Introduction

Though survival is improving for peroxisomal biogenesis disorders and more subtle defects are now diagnosed, most still present in the neonatal period or in infancy. This is also true for most single enzyme peroxisomal deficiencies. Only one group of disorders presents later, with the onset of symptoms often in early teenage years but, due to delays in diagnosis, many are not identified until they reach adulthood. In contrast to the neuropsychiatric or endocrine presentation associated with adrenoleukodystrophy, these peroxisomal disorders present as central and peripheral neuropathies—a neuro-ophthalmic picture. They are often termed Refsum’s disease though, given the multiple underlying genetic defects, it would be better to refer to them as Refsum’s syndrome. The syndrome comprises three genetic disorders: phytanoyl-CoA hydroxylase deficiency (classical adult Refsum’s disease), atypical rhizomelic chondrodysplasia punctata type 1, and the newly described α‎-methyl-acylCoA racemase deficiency.

Historical perspective

Adult Refsum’s disease (OMIM 266510), also called heredopathia atactica polyneuritiformis, is a hereditary sensory motor neuropathy type IV. It was first described in 1947, but only recognized as a syndrome by Refsum in 1962. He described a constellation of signs comprised of retinitis pigmentosa, anosmia, deafness, ataxia, and polyneuropathy allied with raised levels of protein in the cerebrospinal fluid. The biochemical defect was identified in 1963 when phytanic acid was noted in the plasma of affected patients and defective α‎-oxidation was later suggested as the cause of adult Refsum’s disease. This disease was thought to be unifactorial with admittedly some rare aberrant complementation studies until 1995 when, after the localization of the gene for phytanoyl-CoA hydroxylase, up to 50% of cases in one series were shown not to be linked to chromosome 10 but to chromosome 6. Eventually the novel defect was identified as a variant of rhizomelic chondrodysplasia punctata type 1 and caused by mutations in peroxin 7. In parallel with this discovery three patients were described in 1997 with a phenotype of sensory neuropathy and a subtle bile acid disorder but whose families included siblings with a Refsum’s-like syndrome which was identified as due to a deficiency in α‎-methylacyl-CoA racemase. A clinical phenocopy associated with polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) (OMIM 612674) has recently been described. In contrast to other Refsum-like syndromes, phytanic acid levels are normal in this condition.

Clinical features

In contrast to Zellweger’s syndrome (OMIM 214100), neonatal adrenoleukodystrophy (OMIM 202370), infantile Refsum’s’s disease (OMIM 266500), and rhizomelic chondrodysplasia (OMIM 601757), adult Refsum’s disease usually presents in late childhood with progressive deterioration of night vision, the occurrence of progressive retinitis pigmentosa and anosmia (see Fig. 12.9.1). Anosmia, contrary to early reports, is a constant feature of adult Refsum’s disease. After 10 to 15 years, deafness, ataxia, polyneuropathy, ichthyosis, and cardiac arrhythmias can occur. Short metacarpals or metatarsals are found in about one-third of patients. Rare findings include psychiatric disturbance and proteinuria. Premature death may result from cardiac arrhythmias.

Fig. 12.9.1 Cumulative incidence of clinical features on presentation of 15 patients with Refsum’s’s disease. RP, retinitis pigmentosa.

Fig. 12.9.1
Cumulative incidence of clinical features on presentation of 15 patients with Refsum’s’s disease. RP, retinitis pigmentosa.

(From Wierzbicki AS, et al. (2002). Refsum’s disease: a peroxisomal disorder affecting phytanic acid alpha-oxidation. J Neurochem, 80, 727–35, with permission.)

α‎-Methylacyl-CoA racemase (OMIM 604489) presents with adult-onset sensorimotor neuropathy. It may be accompanied by retinitis pigmentosa, visual field restriction and loss of acuity, axonal sensorimotor neuropathy, and myopathy-like adult Refsum’s disease. Other features described have included primary hypogonadism, hypothyroidism, spastic paraparesis, epileptic seizures, and mild developmental delay. More severe childhood-onset cases have shown a phenotype of defects in bile acid synthesis allied with fat-soluble vitamin deficiencies, coagulopathy, and cholestatic liver disease and a resemblance to a Niemann–Pick type C phenotype. PHARC shares many clinical features of Refsum’s disease but lacks the anosmia and possibly the osteological changes. Some mitochondrial disorders in the Leigh syndrome spectrum, including neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP), caused in many cases by mutations in mitochondrial MT-ATP6, may also share some clinical features with adult Refsum’s disease.

Differential diagnosis

The differential diagnoses of the neuropathic disorders and relevant signs and investigations are shown in Tables 12.9.3 and 12.9.4. With classical adult Refsum’s disease, the differential diagnosis includes the various genetic retinitis pigmentosa syndromes if neurological signs are subtle and other rare neurological disorders (Table 12.9.5).

Table 12.9.3 Differential diagnosis of treatable adult neuropathies caused by inborn errors of metabolism

Disease

Onset

Neurology

Signs

Chemistry

Treatment

Screening

Fabry’s disease

10–20

Small fibre Sensory

Stroke; cardiomyopathy; renal

Low α‎-galactocerebrosidase

ERT

WBC α‎-Gal

Serine deficiency

10–20

Axonal

Growth delay; ichthyosis

Low CSF/plasma serine

Serine

Plasma amino acids

Cerebrotendinous xanthomatosis

10–40

Axonal, Demyelination, Sensorimotor

Mental retardation; ataxia, spastic paraperesis. Tendon xanthomata

Cholestanol

Chenodeoxycholate

Cholestanol

Adult Refsum’s disease/syndrome

10–50

Demyelination Sensorimotor

Retinitis pigmentosa, ataxia, anosmia

Phytanic acid

Low phytanic acid diet

Phytanic acid

Porphyrias

10–50

All

Neuropsychiatric Dermatological

PBG and δ‎ALA

Various

PBG and δ‎ALA

Wilson’s disease

15–50

Axonal Demyelination Sensorimotor

Movement disorder

Copper/Caeruloplasmin

Chelation

Copper/caeruloplasmin

CSF, cerebrospinal fluid; δ‎ALA, δ‎-aminolaevulanic acid; PBG, porphobilinogen.

Reproduced from Sebel F et al (2007) Peripheral neuropathy and inborn errors of metabolism in adults. J Inherit Metab Dis, 30, 642–53, with permission.

Table 12.9.4 Differential diagnosis of other adult neuropathies caused by inborn errors of metabolism.

Disease

Age of onset

Neuropathy

Signs

Chemistry

Treatment

Screening

Mitochondrial myopathy

15–50

All

Retinitis pigmentosa, epilepsy, ataxia

CSF/plasma lactate

None

Lactate, muscle biopsy

Metachromatic leukodystrophy

15–50

Demyelination Sensorimotor

Psychiatry, ataxia

Aryl-sulphatase A

None/Bone marrow transplant

Aryl-sulphatase A

Krabbe’s disease

15–50

Demyelination Sensorimotor

Spastic paraparesis

WBC galacto-cerebrosidase

None/Bone marrow transplant

WBC galacto-cerebrosidase

GM2 gangliosidosis

15–50

All

Psychiatry; ataxia,

Hexosaminidase

None

WBC hexosaminidase

AMACR

10–50

Demyelination Sensorimotor

Retinitis pigmentosa, ataxia, anosmia, IQ

Pristanic acid, D/THCA

Low PA diet

Pristanic acid

Abetalipoproteinaemia

5–20

Axonal, Sensory, Sensorimotor

Ataxia, movement disorder, retinitis pigmentosa, acanthocytes

Low cholesterol, Low apolipoprotein B, vitamins A and E

Vitamins A and E

Apolipoprotein B

Vitamin E deficiency

10–20

Axonal, Demyelination Sensorimotor

Ataxia, movement disorder, retinitis pigmentosa, acanthocytes

Vitamin E

Vitamin E

Vitamin E

Homocysteine metabolism (CblC)

15–50

Axonal, motor neuron disease Sensorimotor

Psychiatric, stroke, leukoencephalopathy; Macrocytosis

Homocysteine; methylmalonic acid

Folate, vitamins B12 and B6, betaine

Homocysteine

X-ALD

15–50

Axonal, demyelination Sensorimotor

Neuropsychiatric leukoencephalopathy; adrenal failure

Very long chain fatty acids

?Lorenzo’s oil

Very long chain fatty acids

NARP

5–20

Demyeliation, sensorimotor

Retinitis pigmentosa ataxia

Mitochondrial—MT-ATP6

None; supportive

Mitochondrial DNA

PHARC

10–30

Demyeliation, sensorimotor

Retinitis pigmentosa ataxia, cataract

Endocannabinoid(?)

None

None

AMACR, α‎-methylacyl-CoA racemase; WBC, white blood cell.

Adapted from Sedel F, et al. (2007). Peripheral neuropathy and inborn errors of metabolism in adults. J Inherit Metab Dis, 30, 642–53, with permission.

Table 12.9.5 Differential diagnosis of retinitis with neurological signs (apart from Adult Refsum disease)

Presentation

OMIM

Neurological and other signs

Abetalipoproteinaemia

200100

Ataxia, movement disorder, retinitis pigmentosa, acanthocytes

Vitamin E deficiency

600415

Ornithine aminotransferase deficiency

258870

Gyeate atrophy

Myopathy

Usher’s syndrome Ia

276900

Congenital deafness, ataxia

Usher’s syndromes II

276901

Moderate progressive deafness

Bardet–Biedl–Moon syndrome

209900

Polydactyly

Truncal obesity

Hypogonadism

Short stature

Mental retardation

Kearns–Sayre syndrome

530000

Ophthalmoplegia

Cardiomyopathy

Ceroid lipofuscinosis (Batten’s disease)

204300

Seizures

Dyskinesia

Dementia

X-linked macular degeneration

304020

Ataxia

Myoclonic encephalopathy

NARP

551500

Neurogenic proximal muscle weakness

Ataxia

Dementia

Seizures

PHARC

612674

Polyneuropathy

Hearing loss

Ataxia

Cataract

Aetiology

Phytanic acid (3R,S,7R,11R,15-tetramethylhexadecanoic acid) is an isoprenoid lipid derived from the phytol side chain of chlorophylls by bacterial degradation in ruminants, invertebrates, or pelagic fish (see Fig. 12.9.2). Phytol can be oxidized to an unsaturated fatty acid, phytenic acid, and this is saturated to phytanic acid by a pathway involving fatty aldehyde dehydrogenase 10 (FALDH-10) in microsomes. The significance of this pathway in humans is unclear though high phytanic acid levels have been described in some patients deficient in FALDH-10 with Sjögren–Larsson syndrome. Most phytanic acid is ingested from the adipose tissue and muscle of herbivores or pelagic fish. The average human daily dietary intake of phytanic acid in Western societies is between 50 and 100 mg, of which about 50% is absorbed and metabolized.

Phytanic acid is transported in plasma bound to very low density lipoprotein and later low density lipoprotein, with its elimination allied to reverse cholesterol transport (high density lipoprotein). Phytanic acid is preferentially taken up by the liver and may account for up to 50% of the free fatty acid pool in hepatocytes. This pool is labile and can be acutely mobilized by stress, infection, or starvation, resulting in rapid phytanic acid release. Plasma phytanic acid concentrations are less than 10% of the levels found in adipose tissue and neurons, which accumulate phytanic acid because of its hydrophobicity. The elimination half-life of total body phytanic acid is usually between 1 and 2 years.

Most fatty acids are metabolized by the β‎-oxidation pathways in peroxisomes and mitochondria. Phytanic acid cannot be metabolized by this route owing to the presence of a β‎-methyl group. Instead, phytanic acid is metabolized either by α‎-oxidation to pristanic acid, or by ω‎-oxidation from the other end of the molecule. Using radiolabelled [14C]-phytanic acid as a substrate, an enzyme activity responsible for the α‎-oxidation of phytanic acid in cell lysates was described in 1967. This activity was eventually localized within peroxisomes and, after 30 years, the pathway responsible for α‎-oxidation has been clarified.

Alpha oxidation of phytanic acid

Most phytanic acid metabolism occurs in the liver and kidney by α‎-oxidation, though skin fibroblasts are used for clinical diagnostic purposes. Phytanic acid from plasma enters the peroxisome in association with the sterol carrier protein-2 (SCP-2) and is metabolized by a four-step initial α‎-oxidation pathway. Unusually, it appears this pathway can metabolize two stereoisomers of its substrate equally well. One carbon atom is then removed from the latter in a lyase reaction to give pristanal and formyl-CoA. Pristanal is then oxidized to pristanic acid which is thio-esterified using CoA to give a racemic mixture. The action of a α‎-methylacyl-CoA racemase converts the (2R)-epimer to the (2S)-epimer. Further degradation of (2S)-pristanic acid by the stereospecific β‎-oxidation pathway then occurs, with the release of propionyl and acetyl-CoA units. Further β‎-oxidation reactions (including epimerization) are required to generate the dimethylundecanoic and dimethylnonanoic and methyl-heptanoic acid derivatives, which are finally exported for mitochondrial β‎-oxidation.

Molecular genetics

The defect in adult Refsum’s disease was soon identified as being due to the lack of an α‎-oxidase. It took 30 years for the enzyme responsible, phytanoyl CoA-hydroxylase, to be identified. Two groups identified the gene for phytanoyl CoA-hydroxylase simultaneously in 1997. The phytanoyl CoA-hydroxylase gene includes nine exons and codes for a 338 amino acid protein including the 30 amino acid signal domain, which is cleaved on entry into the peroxisome. Like all the peroxisomal targeting sequence type 2 proteins, phytanoyl CoA-hydroxylase is transported into the peroxisomes by the protein transporter peroxin 7. Deficiency in this transporter is responsible for rhizomelic chondrodysplasia punctata type 1. Phytanoyl CoA-hydroxylase is an iron (II) and 2-oxoglutarate-dependent oxygenase, with little overall sequence similarity to other human oxygenases. Numerous point and splice mutations in phytanoyl CoA-hydroxylase have now been described in adult Refsum’s disease patients, many of which affect 2-oxoglutarate conversion. Significantly, all cause complete inactivation of the protein; no partial function mutations have yet been identified.

Genetic mapping studies have shown that in most cases, but not all, classical adult Refsum’s disease maps to chromosome 10. The locus for the second form of adult Refsum’s disease, comprising about 10% of cases, was localized to chromosome 6q22–24 and biochemical studies of fibroblasts from patients with adult Refsum’s disease established that these patients have subtle deficiencies of peroxisomal targeting sequence type-2 dependent enzyme functions (plasmalogen synthesis) consistent with mild variants of rhizomelic chondrodysplasia punctata, though they lack any clinical signs specific to childhood-onset rhizomelic chondrodysplasia punctata. Ironically, one of the original patients described with adult Refsum’s disease turned out to have the rhizomelic chondrodysplasia punctata variant. A limited number of mutations have been described that cause Refsum’s–rhizomelic chondrodysplasia punctata and it is unclear why these mutations should preferentially lead to mislocalization of phytanoyl CoA-hydroxylase in contrast to other peroxin 7 imported proteins. A third locus for adult Refsum’s disease has recently been described on chromosome 20p11.21-q12 in a consanguineous family but the causative gene remains to be identified.

Disordered ω‎-oxidation

Patients with adult Refsum’s disease are unable to detoxify phytanic acid by α‎-oxidation, and so the ω‎-oxidation pathway is the only metabolic pathway available for its degradation. This pathway produces 3-methyladipic acid as the final metabolite, which is excreted in the urine. Thus, 3-methyladipic acid concentrations can be used as an index of the molar activity of the ω‎-oxidation pathway. After ingestion of a test load of phytanic acid, 3-methyladipic acid is detected in the urine of healthy controls and adult Refsum’s disease heterozygotes showing that ω‎-oxidation plays a significant role in postprandial metabolism of phytanic acid in humans.

The activity of the ω‎-oxidation pathway is approximately doubled in patients with adult Refsum’s disease, but this microsomal pathway has considerable reserve capacity. The balance of intake of phytanic acid and its ω‎-oxidation is likely to determine long-term concentrations of the lipid. Patients with adult Refsum’s disease often clinically relapse during episodes of illness or drastic weight loss. Fasting induces ketosis and lipolysis and acute mobilization of phytanic acid in hepatocyte and adipocyte fatty acid pools. This process can induce a release of 5000 mg (c.15 mmol) per day of phytanic acid (50 times normal). In experimental ketosis, following acute starvation, phytanic acid doubled in 29 h in patients with adult Refsum’s disease and a 80% rise was seen in urinary 3-methyladipic acid levels, indicating that ω‎-oxidation was buffering part of this rise. Phytanic acid concentrations can exceed the capacity of the residual α‎- and ω‎-oxidation pathways. Excess phytanic acid is excreted by low-affinity pathways. Phytanic acid can be glucuronidated and it can also be lost nonspecifically in the urine as nephropathy is a feature of adult Refsum’s disease.

The enzymology of the ω‎-oxidation pathway in adult Refsum’s disease has been clarified and occurs through the microsomal cytochrome P450 (CYP) 4A system as well as the peroxisome. The capacity of the ω‎-oxidation pathway has been measured by the excretion of 2,6-dimethyloctanedioic acid (the C10 ω‎-2-methyl thioester derivative of phytanic acid) at 30 mg phytanic acid (89 µmol) per day. However, other studies measuring 3-methyladipic acid excretion showed a far lower capacity of 6.9 mg (20.4 µmol) per day. These differences in activity may reflect the metabolic fates of the respective markers. Both 2,6-dimethyloctanedioic acid and 3-hexanedioic acid are products of the initial steps of ω‎-oxidation and may be dependent on carnitine ester formation for activation and further metabolism. The initial steps of ω‎-oxidation appear to have a greater capacity than that of the whole pathway when measured by the final product 3-methyladipic acid.

Molecular toxicology of Refsum’s syndrome

The exact mechanism of the toxicity of phytanic acid to neuronal, cardiac, and bone tissue is gradually being clarified. Structural homology between phytanic acid and vitamin A, vitamin E, geranyl-pyrophosphate, and farnesyl pyrophosphate has been noted and it has been suggested that phytanic acid may have a role in the regulation of isoprenoid metabolism and protein prenylation. Recent studies have identified that phytanic acid and also pristanic acid are direct toxins to mitochondria and it has been found that phytanic acid has a rotenone-like action in uncoupling complex I in the oxidative phosphorylation chain in the mitochondrial inner membrane, with subsequent likely production of reactive oxygen species, causes secondary calcium-driven changes through GPR40 and induces apoptosis in neuronal cells. This metabolic toxicity may explain why neuronal or allied retinal pigment tissues rich in mitochondria are the prime tissues affected in adult Refsum’s disease.

The molecular toxicology of pristanic acid is unknown, although it is likely that the mild ophthalmic features seen in some cases may relate to phytanic acid toxicity as for phytanoyl CoA-hydroxylase deficiency. Although both di- and trihydroxycholestanoic acids levels are elevated in α‎-methylacyl-CoA racemase, there is no phenotype of itching associated with this disorder. The cause of the sensory neuropathy in α‎-methylacyl-CoA racemase still remains to be determined.

Epidemiology

Neuropathic adult peroxisomal disorders are rare, with a prevalence of 1 in 106 in Europe and, for unexplained reasons, 10-fold less in the United States of America. As with all recessive conditions, they are more common in cultures or localities with strong founder effects where consanguineous marriages are frequent. The classical Refsum’s phenotype is usually found in genetic ophthalmic services where it may represent 1% of retinitis pigmentosa cases. No surveys have been performed on the incidence of α‎-methylacyl-CoA racemase among patients with neuropathy.

Clinical investigation

The key investigations in the case of suspected neuropathic adult Refsum’s disease are the measurement of phytanic acid (for adult Refsum’s disease) and pristanic acid (for suspected α‎-methylacyl-CoA racemase). These are diagnostic.

For clinical staging purposes, electroretinograms are often performed but often show flat responses characteristic of well-established retinitis pigmentosa. Visual fields should be assessed regularly as functional diplopia is a long-term complication of adult Refsum’s disease. Slit-lamp examination for cataracts is also indicated, as these can be treated. Ideally, retinal photography should be performed so that the extent of retinitis pigmentosa and its progression can be monitored on a long term basis. Anosmia can be detected by screening using the standard four-bottle smell test, but is best quantified by more extensive profiles, e.g. the University of Pennsylvania smell identification test. Auditory function should be assessed by auditory evoked potentials and hearing tests and monitored every 5 years. Peripheral neuropathy should be investigated by peripheral nerve conduction studies for somatosensory potentials and electromyography. A nonspecific demyelination pattern is typical of adult Refsum’s disease. Osteo- or chondrodysplasia is best identified by a radiological survey of hands and feet for short metatarsals and knee radiology for signs of current or previous chondrodysplasia.

Subtler signs that may accompany these definitive tests include an electrolyte profile showing mild hypokalaemia and a Fanconi-like aminoaciduria which can occur in adult Refsum’s disease. Liver function tests should be performed. If bilirubin is raised or α‎-methylacyl-CoA racemase is suspected, a detailed bile acid profile should be performed by mass spectrometric methods. As the differential diagnoses include vitamin deficiencies, vitamin A and E levels should be measured to exclude retinol-deficiency retinopathy and tocopherol-deficient ataxia. Vitamin B12 and folate determinates are used to exclude cobalamin/folate deficient neuropathy.

To differentiate phytanoyl-CoA hydroxylase from peroxin 7 adult Refsum’s disease, it is necessary to measure plasma VLCFAs and plasmalogens. However, often the deficiencies are subtle and these investigations may appear normal. For a definitive diagnosis, a skin biopsy should be taken, fibroblasts grown, and detailed enzyme and immunofluorescence profiles examined in a specialist peroxisomal laboratory.

Criteria for diagnosis

The pathognomic finding in adult Refsum’s disease is greatly elevated phytanic acid concentrations in the plasma (>200 µmol/litre; normal <30 µmol/litre), in contrast to other peroxisomal disorders where levels are usually lower and other metabolic abnormalities are also present. Unlike in rhizomelic chondrodysplasia punctata or the peroxisomal biogenesis disorders, no intellectual defects are seen, bone abnormalities are mild (if present at all), and there is no defect in plasmalogen synthesis. In infantile Refsum’s disease, which is a mild clinical variant of the peroxisomal biogenesis disorder encompassing Zellweger’s disease as its most severe form, numerous subtle peroxisomal defects are present and the condition presents from birth.

In α‎-methylacyl-CoA racemase neuropathy, the pathognomic findings are raised levels of pristanic acid (>100 µmol/litre) allied with increases in di- and trihydroxycholestanoic acids. A secondary elevation of phytanic acid may be seen, but levels are usually between 50 and 100 µmol/litre.

Treatment

Long-term prospects for the treatment of adult Refsum’s disease (or at least for some forms) are good as it is one of the few inherited disorders of metabolism with an exogenous precipitating cause. The disease is treated symptomatically by restriction of phytanic acid intake in the diet or its elimination by plasmapheresis or apheresis. These regimes reduce plasma phytanic acid levels by between 50 and 70%, to values typically around 100 to 300 µmol/litre, and can eliminate phytanic acid completely from fat stores in some patients. Treatment successfully resolves symptoms of ichthyosis, sensory neuropathy, and ataxia in approximately that order. However, it has uncertain effects on the progression of retinitis pigmentosa, anosmia, or deafness although it seems to stabilize these signs.

Prognosis

The prognosis in adult Refsum’s disease depends on the degree to which phytanic acid concentrations are decreased. In untreated disease, presentation is with progressive weakness and neuropathy usually following an acute infective illness which leads to anorexia and acute hepatic phytanic acid release exacerbating the condition. Concentrations of phytanic acid in the plasma usually exceed 1000 µmol/litre. Left untreated, cardiomyopathy and sudden death can occur. If phytanic acid levels are reduced by plasmapheresis and by adequate parenteral nutrition, and then a low phytanic acid diet is followed, prognosis is good. Any myopathy usually resolves within 2 to 3 weeks, though acute visual and auditory deterioration may be irrecoverable. In long-term cases patients are blind, deaf, and anosmic, have extensive peripheral myopathy, and are often wheelchair bound.

In acute adult Refsum’s disease, once phytanic acid levels fall to less than 500 µmol/litre, ichthyosis resolves followed by improvement in myopathy and neuropathy. If phytanic acid levels can be restored to normal values, then it is likely that ophthalmological changes will be minimal or slow, but sudden step-like deteriorations can occur. The principal long-term disability is increasing loss of visual field with subsequent diplopia and progressive cataract formation. Auditory function generally remains good unless phytanic acid levels are substantially raised, in which case audiological deterioration occurs with the need for cochlear implants. Although acute myopathy resolves, patients may have muscle spasms or contractures which may be either related to the adult Refsum’s disease or secondary to the osteodystrophy. Splints and the surgical correction of osteopathy may be required.

Other issues

Adult Refsum’s disease is a potentially treatable cause of retinitis pigmentosa or neuropathy. The average delay to diagnosis is 12 years and a simple biochemical screening test exists for these disorders. Given that earlier implementation of dietary restriction of phytanic acid would likely arrest the disease process before retinitis is established, screening for phytanic and pristanic acidaemias should be considered as an important investigation in retinitis pigmentosa or peripheral neuropathy.

Future developments

The causes of neuropathic adult peroxisomal disorders are incompletely delineated. Cases of pristanic acidaemia with an adult Refsum’s disease phenotype exist for which no cause has yet been found. Similarly, all cases of adult Refsum’s disease currently described are null-function variants, so the phenotype associated with low partial function has not been identified. It may be entirely normal, but it is possible that some cases of retinal dystrophy or peripheral neuropathy may actually be caused by mild phytanoyl-CoA hydroxylase mutations. No cases of deficiency of phytanic acid lyase have been described although, given the gene location overlapping the biotinidase locus on 3p25, a complex phenotype of adult Refsum’s disease neuropathy and ichthyosis with biotinidase-deficiency induced hypotonia, ataxia, hearing loss, optic atrophy, skin rash, alopecia, and organic aciduria might be expected. Alternatively, this combination may be lethal. A number of lyase enzymes with peroxisomal targeting signal motifs remain to be placed on the α‎-oxidation pathway and these may be associated with neuropathy or retinitis pigmentosa syndromes.

Reduction of dietary phytanic acid is already successful in ameliorating most non-ophthalmic symptoms in long-term studies with diet and to a lesser extent apheresis. Orlistat has been shown to reduce phytanic acid in some patients. Newer, more efficacious, therapies are still required to fully reverse the progression of this disease. The signalling pathways which regulate α‎-oxidation in humans are unclear. In rodents, the retinoid X receptor β‎ and peroxisomal proliferator activating receptor α‎ pathways control α‎-oxidation and thus fibrate (PPAR-α‎ agonist) therapy increases activity, but this does not seem to be true in humans. As ω‎-oxidation is capable of large increases in activity and is principally mediated through cytochrome P450 enzymes, it forms a good candidate for therapeutic interventions to induce enzyme activity and reduce phytanic acid levels in Refsum’s disease. However, at the present time, no drug therapy trials of compounds capable of modulating either the α‎- or the ω‎-oxidation pathways have been conducted in humans.

Further information

Adult Refsum’s Disease Website: information for patients, carers and clinicians: http://refsumdisease.org

United Leukodystrophy Foundation Website: http://www.ulf.org

X-linked Adrenoleukodystrophy Data base: http://www.X-ald.nl

Further reading

Aubourg P, et al. (1993). A two-year trial of oleic and erucic acids (‘Lorenzo’s oil’) as treatment for adrenomyeloneuropathy. N Engl J Med, 329, 745–52. [Original randomized control trial of Lorenzo’s oil in X-ALD.]Find this resource:

    Baldwin EJ, et al. (2010). The effectiveness of long-term dietary therapy in the treatment of adult Refsum disease. J Neurol Neurosurg Psychiatry, 81, 954–7. [Long-term outcomes with dietary treatment in Refsum disease.]Find this resource:

      Braverman NE, Moser AB (2012). Functions of plasmalogen lipids in health and disease. Biochim Biophys Acta, 1822, 1442–52. [Review of the biochemistry of plasmalogens.]Find this resource:

        Brown PJ, et al. (1993). Diet and Refsum’s disease. The determination of phytanic acid and phytol in certain foods and application of this knowledge to the choice of suitable convenience foods for patients with Refsum’s disease. J Hum Nutr Diet, 6, 295–05. [Diet for Refsum’s disease.]Find this resource:

          Brown FR III, et al. (1983). Myelin membrane from adrenoleukodystrophy brain white matter—isolation and physical/chemical properties. J Neurochem, 41, 341–8. [Finding increased very long chain fatty acids in myelin in X-ALD.]Find this resource:

            Budka H, Sluga E, Heiss WD (1976). Spastic paraplegia associated with Addison’s disease: adult variant of adrenoleukodystrophy. J Neurol, 213, 237–50. [Description of adenomyeloneuropathy variant of X-ALD.]Find this resource:

              Busanello EN, et al. (2012). Experimental evidence that pristanic acid disrupts mitochondrial homeostasis in brain of young rats. J Neurosci Res, 90, 597–605. [Mechanism of toxicity of pristanic acid.]Find this resource:

                Cartier N, et al. (2009). Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science, 326, 818–23. [Gene therapy for X-ALD.]Find this resource:

                  Eichler F, et al. (2007). Magnetic resonance imaging detection of lesion progression in adult patients with X-linked adrenoleukodystrophy. Arch Neurol, 64, 659–64. [MRI of X-ALD.]Find this resource:

                    Ferdinandusse S, et al. (2000). Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy. Nat Genet, 24, 188–91. [Description of the genetic defect in α‎-methyl-acylCoA racemase deficiency.]Find this resource:

                      Ferdinandusse S, et al. (2010). Adult peroxisomal acyl-coenzyme A oxidase deficiency with cerebellar and brainstem atrophy. J Neurol Neurosurg Psychiatry, 81, 310–2. [Description of the adult presentation of pseudoneonatal adrenoleukodystrophy.]Find this resource:

                        Fiskerstrand T, et al. (2010). Mutations in ABHD12 cause the neurodegenerative disease PHARC: An inborn error of endocannabinoid metabolism. Am J Hum Genet, 87, 410–7. [Description of the third locus and phenocopy for adult Refsum’s disease.]Find this resource:

                          Goldman JM, et al. (1985). Screening of patients with retinitis pigmentosa for heredopathia atactica polyneuritiformis (Refsum’s disease). Br Med J (Clin Res Ed), 290, 1109–10. [Screening for adult Refsum’s disease in retinitis pigmentosa patients.]Find this resource:

                            Griffin JW, et al. (1977). Adrenomyeloneuropathy: a probable variant of adrenoleukodystrophy. Neurology, 27, 1107–3 [Description of adrenomyeloneuropathy in X-ALD.]Find this resource:

                              Haberfeld W, Spieler F (1910). Zur diffusen Hirn-Rueckmarksclerose im Kindesalter. Dtch Z Nervenh, 40, 436–63. [Original description of X-ALD.]Find this resource:

                                Jangouk P, et al. (2012). Adrenoleukodystrophy in female heterozygotes: underrecognized and undertreated. Mol Genet Metab, 105, 180–5. [Clinical diagnosis of adrenoleukodystrophy in women.]Find this resource:

                                  Jansen GA, et al. (1997). Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene. Nat Genet, 17, 190–93. [Description of genetic defect in adult Refsum’s disease.]Find this resource:

                                    Jansen GA, Waterham HR, Wanders RJ (2004). Molecular basis of Refsum disease: sequence variations in phytanoyl-CoA hydroxylase (PHYH) and the PTS2 receptor (PEX7). Hum Mutat, 23, 209–18. [Mutation spectrum in adult Refsum’s disease.]Find this resource:

                                      Kemp S, et al. (2001). ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: role in diagnosis and clinical correlations. Hum Mutat, 18, 499–515. [Mutation spectrum in X-ALD.]Find this resource:

                                        Kishimoto Y, et al. (1980). Adrenoleukodystrophy: evidence that abnormal very long chain fatty acids of brain cholesterol esters are of exogenous origin. Biochem Biophys Res Commun, 96, 69–76. [Possibility of diet therapy in X-ALD.]Find this resource:

                                          Komen JC, Wanders RJ (2006). Identification of the cytochrome P450 enzymes responsible for the omega-hydroxylation of phytanic acid. FEBS Lett, 580, 3794–98. [Identification of the ω‎-oxidation pathway.]Find this resource:

                                            Kumar AJ, et al. (1995). MR findings in adult-onset adrenoleukodystrophy. Am J Neuroradiol, 16, 1227–37. [MRI findings in X-ALD.]Find this resource:

                                              Mahmood A, et al. (2007). Survival analysis of haematopoietic cell transplantation for childhood cerebral X-linked adrenoleukodystrophy: a comparison study. Lancet Neurol, 6, 687–92. [Outcomes of bone marrow transplantation in X-ALD.]Find this resource:

                                                Mihalik SJ, et al. (1997). Identification of PAHX, a Refsum’s disease gene. Nat Genet, 17, 185–89. [Description of gene defect in adult Refsum’s disease.]Find this resource:

                                                  Morita M, Imanaka T (2012). Peroxisomal ABC transporters: structure, function and role in disease. Biochim Biophys Acta, 1822, 1387–96. [Review of peroxisomal ABC transporters.]Find this resource:

                                                    Moser AB, et al. (1999). Plasma very long chain fatty acids in 3000 peroxisome disease patients and 29,000 controls. Ann Neurol, 45, 100–10. [Screening for peroxisomal disorders and X-ALD.]Find this resource:

                                                      Moser HW, et al. (1987). The adrenoleukodsytrophies. Crit Rev Neurobiol, 3, 29–88. [Clinical survey of X-ALD.]Find this resource:

                                                        Moser HW, et al. (1991). Clinical aspects of adrenoleukodystrophy and adrenomyeloneuropathy. Dev Neurosci, 13, 254–61. [Signs in X-ALD heterozygotes.]Find this resource:

                                                          Moser HW, et al. (2005). Follow-up of 89 asymptomatic patients with adrenoleukodystrophy treated with Lorenzo’s oil. Arch Neurol, 62, 1073–80. [Long-term outcomes with Lorenzo’s oil.]Find this resource:

                                                            Moser HW, Mahmood A, Raymond GV (2007). X-linked adrenoleukodystrophy. Nat Clin Pract Neurol, 3, 140–51. [Use of bone marrow transplant in X-ALD.]Find this resource:

                                                              Mosser J, et al. (1993). Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature, 361, 726–30. [Description of X-ALD gene as an ABC transporter.]Find this resource:

                                                                Mukherji M, et al. (2001). Structure-function analysis of phytanoyl-CoA 2-hydroxylase mutations causing Refsum’s’s disease. Hum Mol Genet, 10, 1971–82. [Structure function correlation for phytanoyl-CoA hydroxylase.]Find this resource:

                                                                  Mukherji M, et al. (2003). The chemical biology of branched-chain lipid metabolism. Prog Lipid Res, 42, 359–76. [Review of the α‎-oxidation pathway.]Find this resource:

                                                                    National Center for Biotechnology Information. Online Mendelian Inheritance in Man (OMIM) database. http://www.ncbi.nlm.nih.gov/omim/

                                                                    Odone A, Odone M (1989). Lorenzo’s oil. A new treatment for adrenoleukodystrophy. J Pediatr Neurosci, 5, 55–60. [Original description of Lorenzo’s oil.]Find this resource:

                                                                      Perera NJ, et al. (2011). Refsum’s disease—use of the intestinal lipase inhibitor, orlistat, as a novel therapeutic approach to a complex disorder. J Obes, 2011. [Additional possible therapy for Refsum disease.]Find this resource:

                                                                        Powers JM, Schaumburg HH (1974). Adrenoleukodystrophy (sex-linked Schilder’s disease). A pathogenetic hypothesis based on ultrastructural lesions in adrenal cortex, peripheral nerves and testis. Am J Path, 76, 481–91. [A hypothesis for X-ALD.]Find this resource:

                                                                          Prescott AG, Lloyd MD (2000). The iron(II), 2-oxoacid-dependent dioxygenases and their role in metabolism. Nat Prod Rep, 17, 367–83. [Review of the role of oxygenases.]Find this resource:

                                                                            Purdue PE, et al. (1999). Rhizomelic chondrodysplasia punctata, a peroxisomal biogenesis disorder caused by defects in Pex7p, a peroxisomal protein import receptor: a minireview. Neurochem Res, 24, 581–86. [Review of rhizomelic chondrodysplasia punctata.]Find this resource:

                                                                              Refsum’s S (1946). Heredopathia atactica polyneuritiformis. Acta Psychiatr Scand, 38 Suppl, 9–15. [Original clinical description of adult Refsum’s disease.]Find this resource:

                                                                                Rizzo WB, et al. (1986). Adrenoleukodystrophy: oleic acid lowers fibroblast saturated C22-C26 fatty acids. Neurology, 36, 357–61. [Exogenous fatty acids can affect C22:C26 ratios.]Find this resource:

                                                                                  Schilder P (1924). Die Encephalitis periaxalis diffusa. Arch Psychiatr Nervenkr, 71, 327–35. [Original description of full spectrum X-ALD.]Find this resource:

                                                                                    Schonfeld P, Reiser G (2006). Rotenone-like action of the branched-chain phytanic acid induces oxidative stress in mitochondria. J Biol Chem, 281, 7136–42. [Neurotoxicology of phytanic acid.]Find this resource:

                                                                                      Schlüter A, et al. (2012). Functional genomic analysis unravels a metabolic-inflammatory interplay in adrenoleukodystrophy. Hum Mol Genet, 21, 1062–77. [Transcriptome analysis of x-ALD variants.]Find this resource:

                                                                                        Sedel F, et al. (2007a). Psychiatric manifestations revealing inborn errors of metabolism in adolescents and adults. J Inherit Metab Dis, 30, 631–41. [Review of psychiatric presentations of inborn errors of metabolism.]Find this resource:

                                                                                          Sedel F, et al. (2007b). Peripheral neuropathy and inborn errors of metabolism in adults. J Inherit Metab Dis, 30, 642–53. [Review of neuropathy presentations of inborn errors of metabolism.]Find this resource:

                                                                                            Singh I, et al. (1984). Adrenoleukodystrophy; impaired oxidation of very long chain fatty acids in white blood cells, cultured skin fibroblasts and amniocytes. Pediatr Res, 18, 286–90. [Description of very long chain fatty acid oxidation defect in X-ALD.]Find this resource:

                                                                                              Steinberg D, et al. (1967). Refsum’s disease: nature of the enzyme defect. Science, 156, 1740–42. [Description of the enzyme defect in adult Refsum’s disease.]Find this resource:

                                                                                                van den Brink DM, et al. (2003). Identification of PEX7 as the second gene involved in Refsum’s disease. Am J Hum Genet, 72, 471–77. [Identification of variant rhizomelic chondrodysplasia punctata as adult Refsum’s disease phenocopy.]Find this resource:

                                                                                                  Wanders RJ, Ferdinandusse S (2012). Peroxisomes, peroxisomal diseases, and the hepatotoxicity induced by peroxisomal metabolites. Curr Drug Metab, 13, 1401–11. [Origin of abnormal liver function tests in adrenoleukodystrophies.]Find this resource:

                                                                                                    Waterham HR, Wanders RJ (2012). Metabolic functions and biogenesis of peroxisomes in health and disease. Biochim Biophys Acta, 1822, 1325–30. [Review of peroxisomal biochemistry.]Find this resource:

                                                                                                      Wierzbicki AS, et al. (2002). Refsum’s disease: a peroxisomal disorder affecting phytanic acid alpha-oxidation. J Neurochem, 80, 727–35. [Review of adult Refsum’s disease.]Find this resource:

                                                                                                        Wierzbicki AS, et al. (2003). Metabolism of phytanic acid and 3-methyl-adipic acid excretion in patients with adult Refsum’s disease. J Lipid Res, 44, 1481–88. [Clinical significance of ω‎-oxidation in adult Refsum’s disease.]Find this resource: