Disorders of galactose, pentose, and pyruvate metabolism
Inborn errors of galactose metabolism
Galactose is principally found as free lactose in dairy products; the sugar moiety also occurs as a dietary component in glycoproteins and complex lipids. Three inborn errors of galactose metabolism are recognized:
Galactokinase deficiency (‘galactose diabetes’)—a very rare condition which impairs the assimilation of dietary galactose that is normally initiated by phosphorylation, principally in the liver; the free sugar and its metabolites, galactonic acid and galactitol, appear in plasma and the urine. Conversion of galactose to osmotically active galactitol in tissues causes premature cataracts and occasionally pseudotumor cerebri in infants. The abnormalities may be ameliorated by early institution of a galactose- and lactose-free diet.
Galactose 1-phosphate uridylyltransferase deficiency (classical galactosaemia)—the most important disorder, with an overall estimated frequency of 1 in 47 000 births. High concentrations of galactose in the plasma and tissues lead to aberrant glycosylation of glycoproteins and other glycoconjugates, including lipids. The clinical features are diverse and the pathogenesis remains ill understood. The principal manifestations are a bacteriocidal defect associated with neonatal E. coli sepsis. There is failure to thrive and—in older patients—growth retardation, mental retardation, and hepatomegaly, which without dietary treatment may cause cirrhosis. Disease of the proximal kidney tubule causes the renal Fanconi syndrome and osteomalacia. The diagnosis is made by plasma galactose, galactose 1-phosphate, and red-cell transferase determinations in blood spots obtained after birth. Visceral disease and stunting are mitigated by institution of a lactose- and galactose-free diet, but ovarian failure leading to premature menopause and osteoporosis is common in young girls and women. Ovarian failure is frequent and occurs irrespective of dietary exclusion therapy. Prompt institution of an appropriate diet allows survival into late adult life, but disabling neurological manifestations persist.
Uridine diphosphate-4-epimerase deficiency—a rare but largely harmless disorder, is usually discovered at neonatal screening for galactosaemia.
Essential pentosuria is an asymptomatic autosomal recessive disorder of glucuronate metabolism (principally affecting Ashkenazi Jews) caused by deficiency of hepatic xylitol dehydrogenase which causes the daily appearance of several grams of l-xylulose in the urine.
Disorders of pyruvate metabolism
Deficiency of the pyruvate dehydrogenase complex is the most common inherited disorder which causes lacticacidaemia. Hereditary defects affect the five principal components of this macromolecular complex, most often producing deficiency of the E1α subunit, which is inherited as an X-linked character. Presentation is with overwhelming neonatal acidosis; moderate lactic acidosis with progressive neurological features; or—in male children and young adults—an indolent neurological course without overt acidosis but with episodes of cerebellar ataxia induced by carbohydrate administration.
Pyruvate carboxylase is a biotin-dependent gluconeogenic enzyme deficiency that mainly causes lactate/pyruvate acidosis with a necrotizing encephalopathy resembling Wernicke’s encephalopathy. Hypoglycaemia may complicate intercurrent infections and starvation.
Galactose is derived from the disaccharide lactose (present in milk and dairy products in the diet) by the action of mucosal lactase in the small intestine. The concentration of lactose in human breast milk is approximately 200 mmol/litre. Newborn infants normally receive about one-fifth of their dietary energy supply in the form of galactose, which is derived from the breakdown of this lactose to galactose and glucose in equimolar amounts. Galactose is also complexed with other molecules present in food; it is a component of membrane glycoproteins and glycolipids, and galactosylated sphingolipids are abundant in nervous tissue.
The interconversion of galactose and glucose involves reactions (known as the Leloir pathway) requiring nucleoside (uridine) diphosphate sugar intermediates that lead to the formation of galactose 1-phosphate, which directly enters the main pathways of carbohydrate metabolism (Fig. 220.127.116.11). These intermediates, especially uridine diphosphoglucose, uridine diphosphogalactose, and their aminated derivatives such as uridine diphosphogalactosamine, are critical substrates for the biosynthesis of glycoproteins and glycolipids, including glycosphingolipids; intracellular concentrations of these activated metabolites are influenced by the activity of the enzymes of the Leloir pathway.
Galactose obtained from lactose and other glycoconjugates is present as the β-d-galactose isomer and before it can be further metabolized it must be converted to α-d-galactose in a reaction catalysed by the bidirectional enzyme mutarotase, the crystal structure of which has recently been reported.
The first step in the Leloir pathway involves phosphorylation to form galactose 1-phosphate, which is converted to glucose 1-phosphate and uridine diphosphate-galactose after reaction with the nucleoside diphosphate sugar, uridine diphosphoglucose. Uridine diphosphoglucose is regenerated by the action of uridine diphosphate-galactose-4-epimerase. The presence of this epimerase enables galactose to be produced from glucose for the synthesis of complex glycoconjugates and renders the individual potentially independent of exogenous galactose. Enzymatic defects in the interconversion of these metabolites increase blood and tissue concentrations of galactose, especially after meals containing milk or dairy products.
While the Leloir pathway is clearly the predominant route for galactose metabolism in humans, minor pathways that do not utilize the transferase, epimerase, or galactokinase enzyme system are known to operate: reduction of galactose to galactitol and oxidation to galactonic acid can occur independently, thereby potentially bypassing the metabolic block at the level of the transferase that is responsible for classic galactosaemia. When high concentrations are present, galactose serves as a substrate for enzymes of the polyol pathway catalysed by aldose reductase or l-hexonate dehydrogenase, the former enzyme being responsible for the direct reduction of galactose to galactitol, which is not metabolized any further in the polyol pathway and thus may accumulate in tissues. Raised concentrations of galactitol in blood and urine occur in classic galactosaemia, galactokinase deficiency, and epimerase deficiency. If the transferase is absent, reduction of galactose to galactitol cannot dispose of galactose; rather, it appears likely that formation of galactitol contributes significantly to the pathological effects of galactosaemia. Galactose that accumulates in patients with galactosaemia is in part oxidized to galactonic acid, which may be further degraded to carbon dioxide by the pentose phosphate shunt. A final minor route for galactose breakdown is the pyrophosphorylase pathway, which may dispose of the sugar at about 1% of the rate of the Leloir pathway.
Although they may account for the less severe manifestations of disease in adults who survive with classic galactosaemia, the metabolic capacity of these default pathways is insufficient to mitigate the clinical disease and at the time of writing no effective means to circumvent the defect by this means has been identified.
Galactokinase deficiency: ‘galactose diabetes’
Failure to phosphorylate galactose in the liver and other tissues impairs its clearance from the blood so that the free sugar, as well as its metabolites galactonic acid and galactitol, appear in the urine. Homozygous deficiency of galactokinase occurs with an approximate frequency of 1 in 1 000 000 live births, but it is more frequent in some groups, such as the European Roma gypsy population, in which a single mutant allele of the human galactokinase gene, a (P28T) mutation in GALK1, is prevalent.
Precocious formation of bilateral cataracts in infants and children is characteristic, with some heterozygotes developing cataracts before the age of 40 years. When blood concentrations are high, galactose is taken up by the lens and converted to the end-product galactitol by the action of aldose reductase: subsequent toxic or osmotic effects lead to swelling and irreversible damage to lens fibres. Several infants have presented with benign intracranial hypertension (pseudotumour cerebri), possibly as a result of comparable osmotic effects of galactitol in the brain. Patients with galactokinase deficiency persistently excrete reducing sugar in their urine, but, apart from possible confusion with diabetes mellitus, this has no apparent significance.
Diagnosis and treatment
Galactokinase deficiency should be suspected in infants or children with cataracts, and reducing sugar should be sought in the urine. This sugar will not react with glucose oxidase test strips. Definitive diagnosis by enzymatic assay of galactokinase in erythrocytes or cultured fibroblasts differentiates the disorder from classic galactosaemia and hypergalactosaemia due to vascular disease in the liver. In populations with newborn surveillance for high blood galactose concentration, the deficiency may be detected as a result of finding an abnormal blood galactose concentration with normal transferase and epimerase activities. Definitive enzymatic measurements can be conducted on amniocytes and on cultured skin fibroblasts. Neonatal screening that depends on tests for galactose in the blood will not detect galactokinase deficiency. The human gene for galactokinase maps to chromosome 17q24, with a putative second locus on chromosome 15. Numerous mutations responsible for galactokinase deficiency have been identified in the GALK1 gene at its chromosome 17 locus. Many of these are private, but the so-called Osaka variant, a missense mutation (A198V), was first identified through mass neonatal screening and has a prevalence of 4.1% in Japanese individuals and 2.8% in Koreans; it is uncommon among individuals of Taiwanese and Chinese ancestry. The Osaka GALK1 variant has been reported to occur in 7.8% of Japanese adults with bilateral cataracts, in whom it may represent a true population risk factor.
Lifelong treatment with a lactose-exclusion and galactose-exclusion diet prevents cataract formation, and early cataract formation in infants may be reversed; otherwise surgical removal may be required. Urinary galactitol concentrations, which have been reported to exceed 2500 mmol/mol creatinine, fall to within the reference range for healthy subjects (<3 mmol/mol creatinine) after some weeks of dietary treatment. Although there are numerous reports of bilateral cataracts in heterozygotes for galactokinase deficiency, it remains unclear whether any propensity to cataract formation in later life is prevented by dietary restriction; some authors have suggested that cataracts are more frequent in otherwise healthy individuals who consume abundant dairy products, but have no galactokinase deficiency. In the face of this controversy, it appears to be most prudent to recommend modest restriction of lactose intake in heterozygotes for galactokinase deficiency.
Galactose 1-phosphate uridylyltransferase deficiency: galactosaemia
Unlike individuals in whom galactokinase is deficient, when those who lack uridylyltransferase activity ingest lactose, there is a significant rise in intracellular galactose 1-phosphate as well as blood galactose concentrations. The severe consequences of classic galactosaemia result from the toxic effects of galactose 1-phosphate principally in cells of the liver, proximal renal tubule, and brain. Although the exact mechanism of toxicity is unknown, as in hereditary fructose intolerance, the accumulation of galactose 1-phosphate in a milieu with depleted inorganic phosphate probably inhibits other enzymatic reactions involving phosphorylated intermediates and may lead to purine nucleotide depletion.
Recognition of galactosaemia in early infancy is of paramount importance since the acute effects of galactose poisoning may be reversed by the institution of a lactose-exclusion diet; the birth frequency is about 1 in 50 000 live births but varies greatly according to the population examined. It is notable that the ability of dietary therapy to promote a completely healthy long-term outcome has now been questioned by follow-up studies in large cohorts of patients with classic galactosaemia, and more research is needed to improve our understanding of the pathogenesis of tissue injury in this nutritional disease with neurodevelopmental manifestations as well as the ovarian failure that occurs in affected females.
Clinical and pathological features
Affected infants appear normal at birth, but vomiting or diarrhoea, jaundice, and hepatomegaly usually occur in the first few weeks. There is failure to gain weight, spontaneous bruising, and progressive enlargement of the liver. Cataracts may be apparent at 1 month of age, by which time abdominal distension with ascites has developed. Learning difficulties do not become apparent until later in the first year of life and vary greatly in severity. Many patients with galactosaemia develop severe infections with Escherichia coli during the neonatal period: gram-negative bacterial sepsis may be the first indication of this disorder in young infants. A bactericidal defect in circulating leucocytes has been postulated. In adult patients after reversal of the acute galactose toxicity syndrome, the most obvious sequelae are growth failure, neurological deficit, and, in women, primary ovarian failure with infertility.
A few patients with galactosaemia remain asymptomatic while ingesting milk, but eventually fail to gain weight. Such patients may come to light during childhood or even adult life with varying degrees of learning difficulties and cataracts. Hepatomegaly and intermittent galactosuria are usually present, and often there is a history of feeding difficulties on institution of modified formula feeds during the neonatal period.
The neurological manifestations of classic galactosaemia are highly variable but, despite prompt institution of dietary therapy, a degree of intellectual disability is common in affected children and adults. Characteristic learning difficulties in mathematics and spatial relationships with behavioural deficits have been observed. Children with galactosaemia have a particularly high risk for language impairment. Early dietary lactose may increase the risk for cognitive and language impairments; however, the lack of significant associations of language impairment with days of milk consumption, and other familial and educational risk factors, is consistent with prenatal causation. It appears that the galactose-free diet fails to confer benefit on mental development when instituted beyond the age of 2 years. In follow-up studies of galactosaemic children and adults, a range of neurological deficits, including seizures, apraxia, extrapyramidal disorders, and cerebellar signs, have been documented despite strict dietary measures. In adult galactosaemic patients, recent studies of brain metabolism using positron emission tomography with [18F]-fluorodeoxyglucose revealed extensive regions in which cerebral and cerebellar glucose metabolism was decreased when compared with controls.
Serum tests of liver function are nonspecifically deranged: histological examination shows lobular fibrosis, fatty change, bile ductular proliferation, and progression to frank cirrhosis. A haemorrhagic tendency is an early feature of galactosaemia and the diagnosis should be considered in jaundiced infants with signs of a bleeding diathesis. In the untreated state, biochemical screening tests may suggest a diagnosis of carbohydrate-deficient syndrome since hypoglycosylation and other qualitative abnormalities of serum transferrin N-glycans and other N- and O-linked glycoproteins occur; these abnormalities are largely corrected on transfer to a lactose-exclusion diet.
Involvement of the proximal renal tubule is shown by generalized aminoaciduria and occasionally a full-blown Fanconi syndrome with vacuolation of tubular epithelial cells. Histological examination of the brain shows nonspecific signs of injury with gliosis and Purkinje cell loss in the cerebellum; it appears plausible that the deficiency of uridine diphosphate-galactose will affect the biosynthesis of key galactosphingolipids by uridine diphosphate-galactosylceramide transferase in neural cells. Follow-up studies of female patients with galactosaemia have shown a high incidence of gonadal failure with ovarian atrophy; although this complication appears to be more common in patients in whom dietary therapy was delayed, no clear cause-and-effect relationship has been established. A toxic effect on the fetal ovary due to maternal hypergalactosaemia has been postulated to account for the hypergonadotropic hypogonadism in affected women and girls, but abnormal glycosylation of follicle-stimulating hormone has also been postulated. Pregnancies have occurred in a significant minority of women with classic galactosaemia and they have usually resulted in the birth of healthy infants. No conclusive evidence of gonadal failure has been found in male patients with galactosaemia.
Galactosaemia is transmitted as an autosomal recessive trait with an overall estimated frequency of 1 in 47 000 in liveborn infants. Classic galactosaemia is rare in Japan but frequent in some isolated groups, most notably in the modern Traveller population of Ireland. In this group, screening methods indicate a birth frequency of 1 in 480 compared with 1 in 34 000 in the non-Traveller Irish population. In African American patients from the United States of America a relatively mild disorder has been reported that is probably due to an unstable enzyme variant; uridylyltransferase activity is absent from the red cells of these patients but amounts to some 10% of normal in samples of liver and small intestinal tissue. Patients with the so-called Duarte variant possess about one-half of the normal enzyme activity in erythrocytes but remain asymptomatic.
The human galactosyl-1-phosphate uridylyltransferase gene maps to human chromosome 9p13 and encodes a protein of molecular weight 43 kDa, which exists as a functional homodimer. Molecular analysis of the transferase gene indicates that most patients with classic galactosaemia harbour missense-type mutations and are compound heterozygotes. Numerous variant transferase enzymes are known and, by early 2008, more than 200 disease-associated mutations were reported. Molecular analysis of the transferase gene has identified several widespread mutations; for example one mutant allele (Q188R) is in linkage disequilibrium with a restriction fragment-length polymorphism flanking exon 6 of the gene sequence in multiple populations worldwide, including those of European descent and Irish Travellers. A less frequent mutation of diagnostic significance in white populations is designated R333W; the Duarte transferase mutation has been identified as N314D. Molecular analysis of the transferase gene now renders prenatal diagnosis of at-risk pregnancies possible.
Contemporary studies using gene-expression profiling and proteomic analytical methods have been undertaken in attempts to understand the complex effects of galactosaemia, which may be a consequence of early toxicity or persistently abnormal macromolecular glycoconjugates. Perturbed cell-signaling pathways have been reported by Treacy and colleagues: these include those mediated by mitogen-activated protein kinase (MAPK)—also with effects on regulation of the actin cytoskeleton and ubiquitin-mediated proteolysis. Serum N-glycan profiles and IgG glycosylation in patients treated by the exclusion diet were compared with healthy control sera; these showed increased concentrations of agalactosylated and monogalactosylated structures in the patients and reduced digalactosylated structures. The persistently abnormal glycosylation of serum glycoproteins suggests that metabolic dysregulation and abnormal gene expression occur despite treatment. While preliminary, these studies reported by Coman et al., suggest that while restriction of dietary galactose is essential for survival of galactosaemic patients in the neonatal period, strict exclusion regimens may themselves induce injurious biochemical and genetic changes with long-term consequences on health and tissue modelling and integrity.
Galactosaemia may be suspected in an infant with growth failure, cataracts, liver disease, aminoaciduria, learning difficulties, and especially where reducing sugar is present in the urine. The occurrence of unexplained bacterial sepsis, especially if due to Escherichia coli infection in a newborn infant, may indicate galactosaemia. Cataracts may be detected by slit-lamp examination in the first few days of life.
Since the clinical manifestations of galactosaemia are not specific, it is necessary to consider the diagnosis, especially in countries where neonatal screening for galactosaemia is not routinely carried out. The finding of hypergalactosaemia is not specific for those hereditary galactosaemias due to inherited deficiencies of galactose-metabolizing enzymes. Recent studies in infants show that persistent hypergalactosaemia may commonly be due to portosystemic venous shunts that are often associated with patent ductus venosus or other congenital vascular abnormalities in the liver. Doppler ultrasonography is a convenient noninvasive investigation to search for such shunts in infants.
Definitive diagnosis of hereditary galactosaemia is mandatory, and relies on the determination of galactose 1-phosphate uridylyltransferase activity and other galactose-metabolizing enzymes in red cells, skin fibroblasts, or leucocytes by means of a specific enzymatic assay. This procedure is required to confirm the results of initial screening tests conducted on dried blood spots (Beutler assay); transferase activity in patients with classic galactosaemia is generally less than 1% of the normal reference range. Reliable enzymatic or genetic testing for heterozygotes can be conducted in the parents of a child who died before the diagnosis was confirmed. In particular populations, neonatal screening for elevated blood galactose and galactose 1-phosphate concentrations is carried out routinely. Molecular analysis of the gene encoding galactose 1-phosphate uridylyltransferase in at-risk pregnancies has been requested by some affected families. Neonatal screening for galactosaemia is available in the United States of America and in Europe, but only a small percentage of newborns in the United Kingdom are tested. At the time of writing, no prospective studies have demonstrated whether newborn screening programmes lead to an earlier diagnosis and reduce early morbidity and mortality from galactosaemia, and it seems unlikely that screening will prevent or reduce the late complications in adults. However, several retrospective studies indicate that neonatal screening prevents early deaths in this disease; in one survey 80% of patients who underwent newborn screening were diagnosed by 14 days of age, compared with only 35% of patients who were not tested but who had manifest disease.
Without strict dietary treatment, most patients with galactosaemia die in early infancy, although some may survive with liver disease and learning difficulties beyond childhood. The course of galactosaemia is strikingly altered on withdrawal of lactose (and galactose), although the outcome of neurological disease is often disappointing. Lactose is present in many nondairy foods, and advice from an experienced dietician, as well as meticulous attention to detail, is required to eliminate it completely. In infants, soybean milks or commercial casein hydrolysates are used as milk substitutes, and therapy is monitored by periodic assay of red-cell galactose 1-phosphate concentrations. Soya milk contains galactose equivalents complexed to other molecules (about 15 mg/litre) and there is a trend to adopt a completely galactose-free artificial formula in the treatment of affected infants; however, proof that this biochemically successful strategy induces better long-term outcomes in classic galactosaemia is not available. Despite reports that galactose may be reintroduced as the patient develops, lifelong strict adherence to the exclusion diet should be strongly advocated. In the untreated state, the concentration of red-cell galactose 1-phosphate is above 5 mmol/litre but with close adherence to the diet it falls within a few months to less that 0.25 mmol/litre. Although biochemical monitoring has not been shown closely to predict outcomes, as a rule expert centres recommend that the desired long-term target for blood galactose 1-phosphate concentrations should be less than 0.15 mmol/litre of erythrocytes and monitoring 2 to 3 times per year in the first decade is usually practised.
In subsequent pregnancies of heterozygous mothers who have had affected children, there is evidence that premature cataracts can be avoided in the fetus if the maternal intake of lactose is restricted. In late pregnancy, lactosaemia and lactosuria are common findings and result from the physiological induction of lactose biosynthesis in mammary tissue. In rare cases (see below) there is a risk of self-intoxication when women with homozygous deficiency of the transferase become pregnant and breastfeed, so that additional dietary precautions are needed to maintain metabolic control during lactation.
Maintaining appropriate lifelong care for patients with galactosaemia in specialist clinics shows benefits in the provision of dietary management with expert advice as well as developmental monitoring and assessment of cognitive function that can be matched to educational needs. Regular review in paediatric, transitional, and then adult metabolic specialist centres is critical for many patients who have overt or hidden difficulties with speech or cognition. Review allows for regular metabolic monitoring and serial evaluation of bone mineralization density and vitamin D status, with opportunities to intervene where appropriate to avoid the risk of fragility fractures. The parents of girls and women with galactosaemia will also benefit from the ability to discuss matters related to reproductive health and fertility and obtain the necessary referrals for gynaecological and endocrinological treatment. Although spontaneous conception has been rarely documented in classical galactosemia, most females with the condition will develop primary ovarian insufficiency. Even with neonatal diagnosis and rigorous lifelong restriction of galactose and lactose ingestion, more than 80% of girls and women with classic galactosaemia develop primary or premature ovarian insufficiency—thus consultation about the options to preserve fertility are desirable and often requested. However, there are no clear recomendations about how fertility in such patients can best be preserved—or whether this is advised. With a severely reduced pool of ovarian follicles from an early age, permitting fertility after loss of ovarian function by cryopreservation of ovarian tissue is the only available procedure that is likely to be successful—and only then, in very young (prepubertal) girls. The cryopreservation technique remains experimental and is not generally available in clinical practice; moreover, the procedure carries wth it the risk of damage to remaining ovarian tissue, and thus may jeopardise the viability of remaining ovarian reserve. Moreover, its application at an early age also raises ethical questions in relation to the ultimate capacity of the adult woman with classical galactosaemia to raise children or in some cases to make independent reproductive choices. Uncertainties about attempts to preserve fertility in females and the appreciable but rare chance of spontaneous pregnancy thus warrant caution: indeed, a recent investigation of fertility preservation in this condition has recommended that it should only be offered with appropriate institutional research ethics approval and counselling to girls with classic galactosaemia at a young prepubertal age.
The acute manifestations of galactosaemia and growth failure respond quickly to dietary therapy and cataract formation is prevented. Unfortunately, a proportion of patients have significant neurological deficits despite prompt and conscientious treatment. An international survey of the long-term outcome in 350 patients receiving dietary therapy has been published by Waggoner and colleagues. In a recent report by Treacy and colleagues from Ireland where screening has been in place since 1982, and where the overall live birth incidence of classical galactosaemia in the whole population was about 1 in 16 500. Despite early initiation of dietary treatment, long-term outcomes are often disappointing. In Ireland, nearly one third of patients aged six years and over has IQs of less than 70, and half those over the age of two and a half years have speech or language impairments. As in other series, more than 90% of the Irish females aged 13 years and over suffer from hypergonadotrophic hypogonadism with the consequential risk of decreased fertility. The presence of ovarian failure and elevated galactose 1-phosphate concentrations in patients apparently ingesting no lactose or galactose raises the possibility that an endogenous pathway of galactose 1-phosphate formation from the pyrophosphorylysis of uridine diphosphate-galactose may occur. This may also explain the late emergence of neurological disease in treated patients. Motor and cerebellar defects occur frequently in adult patients with galactosaemia. In a recent cross-sectional study of forty-seven adult patients with classical galactosaemia, thirty-one had evidence of motor impairment with tremor (23 patients), dystonia (23 patients), cerebellar signs (6 patients), and signs of pyramidal tract disease (4 patients). Tremor and dystonia often coexisted. In this series it is notable that non-motor neurological features (cognitive, psychiatric, and speech disorders) and premature ovarian failure were more frequent in patients with motor dysfunction. Up to one third of patients report motor symptoms and may benefit from appropriate symptomatic treatment. Progressive deterioration is frequent and may indicate persistent brain injury. Long-term follow-up and periodic neuropsychiatric as well as physical monitoring is recommended. Recently, several pregnancies have been reported in women who have classic galactosaemia, including subjects homozygous for the Q188R mutation. In such pregnancies, high concentrations of galactitol are found in amniotic fluid but cord blood values have been determined to be within the range found in galactosaemic patients receiving strict dietary therapy. Thus, although maternal galactitol traverses the placenta, it probably does not harm the heterozygous fetus.
Uridine diphosphate-4-epimerase deficiency
Epimerase deficiency is very rare but may be identified during screening for classic galactosaemia. In most cases no symptoms attributable to galactosaemia are apparent and follow-up studies have confirmed the usually benign nature of this anomaly. However, a few cases of marked deficiency of uridine diphosphate-4-epimerase have been discovered in patients otherwise manifesting the classic features of galactosaemia. In the absence of epimerase activity, the individual is dependent on exogenous sources of galactose, since this cannot be derived from glucose. The autosomal recessive nature of this inherited disorder has been confirmed by demonstrating a partial epimerase deficiency in the healthy parents of an affected infant. As a complete deficiency of the epimerase would lead to an absolute lack of uridine diphosphate-galactose for galactosphingolipid synthesis, the ingestion of very small quantities of galactose has been recommended in this unusual disorder so that brain development and biosynthesis of essential galactosides can proceed. Infants with marked generalized epimerase deficiency who are on a diet containing lactose typically become hypotonic, feed poorly, and have vomiting, weight loss, jaundice, hepatomegaly with abnormal serum liver test abnormalities, aminoaciduria, and cataracts. Prompt removal of galactose from their diet should ameliorate or prevents these acute manifestations of the disease.
Because of the dual activity of the epimerase towards uridine diphosphate-acetyl glucosamine as well as uridine diphosphate-glucose, it has been suggested that small supplements of the aminoacetyl galactosamine should also be provided in the diets of patients with uridine diphosphate-galactose-4-epimerase deficiency. This condition may be contrasted with the transferase deficiency that allows the formation of small amounts of endogenous galactose in the presence of an intact epimerase. The gene for human uridine diphosphate-galactose-4-epimerase has been mapped to chromosome 1p36–p35, and numerous mutant alleles have been identified.
Infants should be fed a formula containing only trace quantities of galactose or lactose. Continued dietary restriction of dairy products in older children is recommended. In severe generalized epimerase deficiency-induced galactosemia, restricted dietary galactose appears to correct or prevent the acute signs and symptoms of the disorder but does not influence the developmental delay or learning impairment observed in some children. Infants with peripheral or intermediate epimerase deficiency galactosemia do not exhibit acute sequelae regardless of diet.
The concentration of red-cell galactose 1-phosphate is monitored and estimated tolerable limits are believed to be less than 150 µmol/L; clearly as with patients suffering from classical galactosaemia, it is important also to monitor growth and developmental milestones.
Pentosuria is caused by the excessive renal excretion of l-xylulose. This has no clinical significance except that it may lead to the incorrect diagnosis of diabetes mellitus should tests for reducing sugar be carried out on the urine. Xylulose does not react with urinary test strips based on the glucose oxidase method.
Although pentosuria is a rare autosomal recessive trait, its frequency in Ashkenazi Jews may be as high as 0.05% (but see recent studies below). It is caused by deficiency of l-xylulose reductase, a nicotinamide adenine dinucleotide phosphate-dependent enzyme in the oxidative pathway of glucuronate metabolism, which results in 1 to 4 g xylulose and l-arabitol continuously appearing in the urine; output is greatly enhanced by the ingestion of glucuronic acid or drugs that are excreted as glucuronides. Recently, two distinct point mutations in the human gene (DCXR) encoding L-xylulose reductase that are predicted to inactivate the enzyme by inducing frameshifts (c.583ΔC and c.52(+1)G > A), have been identified in subjects with pentosuria. These individuals were identified by archival investigations of descendants of the original Jewish pedigrees studied in the United States by Pierce et al. collaborating with Dr Arno G Motulsky. The enzyme is present in many cells including red cells and hepatocytes. Several reactions remove the carboxyl carbon atom of d-glucuronic acid to generate the pentose l-xylulose, which is converted to its stereoisomer, d-xylulose. d-Xylulose is phosphorylated to d-xylulose 5-phosphate, which can be converted to hexose phosphates in the reactions of the pentose phosphate shunt. The diagnosis is made definitively in specialized laboratories by confirming the enzymatic defect in erythrocytes, but pentosuria is most readily confirmed by paper chromatographic analysis of urine using n-butanol, ethanol, and water (50:10:40) as the partitioning solvent and orcinol-trichloroacetic acid as a detection agent; the sugar has a high mobility (RF 0.26) and is identified by its red colour on development. Long-term monitoring of 40 individuals with pentosuria over more than 16 years showed no decrease in life expectancy. The combined frequency of the two mutant DCXR alleles in 1,067 Ashkenazi control subjects has been found to be 0.0173, suggesting a pentosuria frequency of approximately one in 3 300 in this population.
Inborn errors of pyruvate metabolism
The organic acids, pyruvate and lactate, are interconvertible intermediates of critical importance in energy metabolism. Pyruvate dehydrogenase is a multienzyme complex located in the matrix of mitochondria: energetically it bridges glycolysis and the Krebs’ tricarboxylic acid cycle by catalyzing the conversion of pyruvate into acetyl CoA. Defective function of the complex is one of the more frequent causes of lactic acidosis and is associated with neurological manifestations that vary with age and gender. Severe defects in pyruvate dehydrogenase activity impeded energy production so that brain development is impaired in utero. As a result, epilepsy and structural brain anomalies occur. Moderate or lesser defects have variable effects such as cognitive delay, ataxia, and seizures. Impaired energy production is linked to development of structural brain anomalies and abnormal metabolism of neurotransmitters. By providing a direct source of acetyl CoA, institution of a ketogenic diet can partially overcome the metabolic block and suppress some of the manifestations of the biochemical defect.
The most frequent defect, PDHA1 deficiency is transmitted as an X-linked disorder with variable expression in females according to the effects of Lyonization. Other defects due to mutations in PDHB and the very rare pyruvate dehydrogenase phosphatase (PDP) deficiency are transmitted as autosomal recessive traits.
Breakdown of pyruvate proceeds by oxidation, first by pyruvate dehydrogenase, then the Krebs cycle, and finally the respiratory chain; anabolic assimilation of pyruvate is mediated by pyruvate carboxylase. Lactate is the product of anaerobic glycolysis and is generated entirely from reduction of pyruvate by lactate dehydrogenase; lactate is disposed of by the reversal of this reaction. Defective metabolism of pyruvate readily leads to the accumulation of lactate and the development of lacticacidaemia.
Pyruvate dehydrogenase deficiency
Deficiency of pyruvate dehydrogenase is the most common cause of lactic acidosis in newborn infants and children, but it is also associated with neurodegenerative syndromes in later life. Pyruvate dehydrogenase exists as a multienzyme complex representing the products of 10 distinct genes. However, defects in one subunit of pyruvate dehydrogenase itself (E1α) account for most patients so far investigated; other defects in dihydrolipoyl transacetylase (E2), dihydrolipoyl dehydrogenase (E3), X-lipoate, or the pyruvate dehydrogenase phosphatase component of the complex have also been reported.
The pyruvate dehydrogenase complex catalyses the conversion of pyruvate to acetyl CoA within mitochondria and is rate-limiting for aerobic metabolism of glucose in the brain; in the adult brain, daily glucose consumption is 125 g. Thus the pyruvate dehydrogenase complex is critical for brain metabolism since this is normally entirely dependent on the oxidative breakdown of glucose. Where the activity of the complex is impaired, accumulated pyruvate may either be reduced to lactate or transaminated to alanine, so that hyperalaninaemia and varying degrees of lacticacidaemia occur. Very rare defects in dihydrolipoyl dehydrogenase are associated with deficiency of branched-chain keto acid dehydrogenase. Failure to carry out oxidative reactions in regions of the cortex and midbrain causes neuronal death; deficiency of four-carbon intermediates may critically impair synthesis of neurotransmitter molecules.
There are three main activities associated in the complex: (1) pyruvate dehydrogenase, a thiamine pyrophosphate-dependent complex (E1); (2) dihydrolipoyl transacetylase (E2); and (3) dihydrolipoyl dehydrogenase (E3). Also associated are a pyruvate dehydrogenase-specific kinase and phosphatase (both involved in overall metabolic regulation of the complex) as well as an essential lipoate-containing protein other than dihydrolipoamide transacetylase in the pyruvate dehydrogenase complex (X-lipoate), which possesses an acyl transfer function.
The combined molecular mass is about 8.5 million and the complex comprises 30 units of E1, 60 units of E2, and 6 units each of E3 and X. The E1 unit is an α2β2 tetramer with subunits of 41 and 36 kDa.
Clinical features and prognosis
The extent of clinical expression of the enzymatic defect is highly variable. There may be fulminant lactic acidosis in the newborn infant; intrauterine neurological development is impaired, marked acidosis (blood lactate >10 mmol/litre) is present at birth, and this disorder is rapidly fatal. In others, lacticacidaemia may not be apparent and the disease comes to light because of intrauterine growth failure, neonatal hypotonia asphyxia, and feeding difficulty; the principal abnormality is progressive psychomotor retardation often accompanied by brainstem injury and disease of the basal ganglia. There is dysgenesis with structural abnormalities of the olivopontocerebellar tract and periventricular grey matter. Cortical atrophy and agenesis of the corpus callosum have also been reported in association with spastic quadriplegia, especially in patients presenting with neonatal acidosis. Blood lactate concentrations do not exceed 10 mmol/litre. Without intensive treatment, death usually occurs in infancy; however, should feeding by gavage be instituted, there is a protracted course with failure of neurological development, microcephaly, quadriplegia, seizures, and blindness. Intermittent cerebellar ataxia or torsion dystonia have been recorded and choreoathetoid movements occur. Involuntary eye movements in children are associated with a progressively deteriorating course.
A milder form of the disorder occurs in defects of the X-linked E1α gene (PDHA1) but because pyruvate dehydrogenase deficiency is of key importance in brain metabolism, expression of disease is observed in females and affected males; this form of pyruvate dehydrogenase complex deficiency is an X-linked dominant disorder—an operational term to indcate expression of disease in most heterozygous females. In boys, however, episodic cerebellar ataxia may be induced by feeding carbohydrate-rich foods or even medicinal glucose; the disorder responds to introduction of a ketogenic diet which supplies the deficient metabolic intermediate, acyl CoA. In these patients, some of whom are otherwise unimpaired and have normal intelligence, blood lactate concentrations may only be trivially elevated. In contrast, in other patients a progressive brainstem disorder occurs, characteristic of Leigh’s disease, with haemorrhagic necrosis and symmetrical spongiform appearances in the periventricular grey matter, thalami, midbrain, pons, medulla, and spinal cord; the mammillary bodies are spared.
There are fascinating similarities between pyruvate dehydrogenase complex deficiency and diseases related to thiamine deficiency with or without induction by exposure to alcohol (ethanol). About one-third of patients with pyruvate dehydrogenase complex deficiency have facial appearances reminiscent of the fetal syndrome due to maternal consumption of excess alcohol; this dysmorphism is characterized by a narrow head, retroussé nose, flared nostrils, and an elongated philtrum; there is frontal bossing of the skull and a broad nasal bridge. In the acquired syndrome, acetaldehyde from the maternal circulation is believed to inhibit pyruvate dehydrogenase in the fetus, and Robinson and colleagues have suggested that low endogenous activity of the pyruvate dehydrogenase complex due to genetic deficiency in the fetus is responsible for the developmental abnormalities. A striking connection between agenesis of the corpus callosum, usually in patients with neonatal pyruvate dehydrogenase deficiency, has been made with the Marchiafava–Bignami syndrome, a condition characterized by degeneration of the corpus callosum and associated with longstanding abuse of alcohol. Finally, in Wernicke’s encephalopathy, the effects of thiamine deficiency and deficiency of the pyruvate dehydrogenase complex on the brain occur principally in the regions of the greatest metabolic activity, especially in the brainstem and basal ganglia. Diminished activity of the pyruvate dehydrogenase complex caused thiamine pyrophosphate deficiency, possibly combined with inhibition by the ethanol metabolite, acetaldehyde, as a plausible common factor in neuropathogenesis.
Recently, mild forms of pyruvate dehydrogenase deficiency due to defects in lipoamide dehydrogenase (E3 component) have been observed. Hereditary spinocerebellar degeneration appearing in early adult life has been attributed to the deficiency of pyruvate dehydrogenase but there is no direct relationship to Friedreich’s ataxia. In patients who present with severe acidosis at birth, subacute necrotizing encephalomyelopathy of the Leigh type has been confirmed at necropsy with cystic appearances principally in the cerebral cortex, basal ganglia, and brainstem.
The most common cause of pyruvate dehydrogenase deficiency is due to a defect in the E1α subunit, a protein encoded on the X chromosome. Although the disease is characteristically more severe in males, manifestations in the heterozygous female are unusually frequent for an X-linked disease and probably reflect the low functional reserve of the enzyme complex in the brain. Neonatal lactic acidosis is more frequent in males. An auxiliary gene for the E1α subunit is localized as a result of retroposition from the X chromosome to the long arm of chromosome 4, but is expressed only during spermatogenesis; its presence, however, indicates the critical need for activity of the complex in nearly all tissues. Causal mutations in the PDHA1 gene on the X chromosome have been described; most appear to be short deletions or duplications and, at present, are not generally applicable for diagnosis. However, analysis of X-chromosome inactivation patterns, by determination of methylation status, has proved useful for the evaluation of enzymatic assays of fibroblasts obtained from obligate carriers or female patients in whom the diagnosis is suspected.
Diagnosis and treatment
The diagnosis is suspected from the presence of severe acidosis at birth. It may also emerge during the investigation of neurological deficits, especially where they are associated with intrauterine growth failure. Routine screening of urine samples for organic acids may identify excessive pyruvate and lactate; hyperammonaemia with citrullinaemia, hyperlysinaemia, and hyperalaninaemia may be found on blood analysis. In patients without clinically evident acidosis, cerebral disease is accompanied by striking elevations of lactate and pyruvate in the cerebrospinal fluid. Mutation analysis of the X-linked PDHA1 gene and determination of the abundance of immunoreactive pyruvate dehydrogenase protein now permits decisive diagnosis of this disease.
The diagnosis of lacticacidaemia may be very challenging, especially when an inborn error of metabolism is responsible. Lactic acid is the product of the anaerobic metabolism of glucose, principally in circulating erythrocytes, skin, kidney medulla, and white skeletal muscle. Excess production of lactic acid is a consequence of numerous disorders that do not have an overt hereditary basis. These include drug overdose (e.g. biguanide antidiabetic agents); hypoxia, ischaemia, and hypotensive shock; overwhelming sepsis; bacterial overgrowth colonization of the small intestine; and liver disease.
Determination of lactate and pyruvate concentrations in cerebrospinal fluid are of critical value and require special conditions for collection, transport, and storage before assay; measurement of glucose, lactate, pyruvate, 3-hydroxybutyrate, and acetoacetate in whole blood, as well as plasma amino acid concentrations should be carried out. Urine organic acid analysis requires the assistance of a specialized laboratory equipped for gas chromatography; increasingly, mass spectrometry is used in major diagnostic centres. Muscle biopsy for mitochondrial studies and determination of the redox state in cultured skin fibroblasts using the lactate:pyruvate ratio may also be valuable, but further specialized studies will require advice from a biochemical and genetics service with experience in the diagnosis of inborn errors of metabolism. The value of referral to an appropriate clinical specialist cannot be overemphasized.
Neuroradiological procedures, including cerebral ultrasonography and CT, reveal ventricular dilatation and cerebral atrophy. In several infant girls with pyruvate dehydrogenase deficiency, MRI showed hypoplasia of the corpus callosum as well as loss of normal white matter signal intensity. Proton magnetic resonance spectroscopy revealed high-abundance signals for brain lactate with decreased intensity of N-acetylaspartate, while phosphorus magnetic resonance spectroscopy of skeletal muscle showed abnormally low muscle phosphorylation potentials, in keeping with the predicted biochemical disturbance. Pathological examination of previously affected siblings shows shrinkage of gyri, with involvement of the medulla shown by loss or hypoplasia of the pyramids. The pathological features of Wernicke’s encephalopathy may be present. The corpus callosum may be absent. Definitive diagnosis, however, depends on genetic and enzymatic studies in skin fibroblasts or blood leucocyte samples.
Institution of a high-fat, low-carbohydrate, ketogenic diet may ameliorate the biochemical abnormalities, but, given the degree of neurological impairment that is normally present at diagnosis, only modest clinical improvement is likely in most patients. However, the degree of recovery cannot be readily predicted in the absence of systematic empirical observation. There is evidence that ketogenic diets containing 50% fat and 20% carbohydrate ameliorate the biochemical disturbance and delay the onset of neurological disease. In the past, ketogenic diets may contain 90% of daily calorie from fat and very unpalatable. Wexler and colleagues showed that initiation of thistreatment earlier in life or in patients with pyruvate dehydrogenase deficiency who were placed on greater carbohydrate restriction had increased longevity and improved mental development. Based on the improved outcomes of patients with identical mutations, it appears that a nearly carbohydrate-free diet initiated shortly after birth may be useful in the treatment of E1 complex deficiency.
Therapeutic responses to the administration of high-dose thiamine given parenterally (50–300 mg daily) have been reported in patients with partial enzymatic deficiency, notably where ataxia and abnormal eye movements reminiscent of Wernicke’s encephalopathy or features indicative of Leigh’s disease were conspicuous. Dichloroacetate, an analogue of pyruvate which inhibits the regulatory effect of pyruvate dehydrogenase kinase and so stimulates pyruvate dehydrogenase activity, has been proposed for the treatment of primary lacticacidaemia, particularly in patients with pyruvate dehydrogenase deficiency. Clinical trials indicate that correction of the biochemical abnormality depends on the molecular defect, and heterogeneity in patient selection may explain the equivocal clinical responses observed in long-term studies. Nonetheless, dichloroacetate appears to be quite well tolerated and deserves consideration in patients who fail to respond to other measures, including the recommended ketogenic diets with high-dose thiamine supplementation. At sustained doses—generally 25 mg/kg/day taken orally, or greater—there is a risk of peripheral neuropathy, neurotoxicity, and gait disturbance and although thiamine was believed to ameliorate this risk, peripheral neuropathy remains a potential hazard. Recent long-term studies in eight patients by Dr Stacpole’s group in Florida USA including those with proven deficiencies of the E1α subunit of the pyruvate dehydrogenase complex or respiratory chain complexes who received oral dichloroacetate (at 12.5 mg/kg/12 h) for nearly 10 to 16.5 years are encouraging. All subjects had participated in randomized controlled trials of DCA and were continued on an open-label chronic safety study in which the agent maintained normal blood lactate concentrations, even in those on largely unrestricted diets. Nerve conduction either did not change or decreased modestly and led to reduction or temporary discontinuation of the drug in three patients with pyruvate dehydrogenase deficiency and other forms of lactic acidosis.
Inborn defects cause hypoglycaemia or profound metabolic acidosis with neurodegenerative features. The enzyme plays important roles also in lipogenesis, in biosynthesis of glycerol in liver and adipose tissue as well as in the functions of brain and pancreatic islet. Pyvuate carboxylase thus has far-reaching anaplerotic functions which are lost when the enzyme is deficient.
Neuronal loss is prominent, although the enzyme is principally expressed in astrocytes and other non-neuronal cells; this suggests that a defect impairs the supply of nutrients that are essential for neuronal survival but which are derived from metabolic activity in astroglia. The manifestations closely resemble those caused by deficiencies of pyruvate dehydrogenase activity and appear to be determined by the degree of residual pyruvate carboxylase activity. A severe form associated with hyperammonaemia, hyperlysinaemia, and citrullinaemia is also recognized, particularly in patients of French descent; survival beyond a few months of age in this variant is rare.
Pyruvate carboxylase, is a biotin-dependent gluconeogenic enzyme which catalyses formation of oxaloacetate from pyruvate in a reaction that is stimulated allosterically by acetyl-CoA. Thus, hypoglycaemia would be expected only after glycogen stores had been depleted. Krebs cycle intermediates may become depleted so that synthesis of neurotransmitters is impaired. There may also be a reduced supply of aspartate for the arginosuccinate synthase reaction of the urea cycle, and hence the association with hyperammonaemia.
Patients with severe deficiency of pyruvate carboxylase may present with Leigh’s syndrome (necrotizing encephalomyopathy with lactate/pyruvate acidosis) or hypotonia and neurological retardation. The presence of ataxia and abnormal ocular movements in life suggest the occurrence of midbrain disease resembling Wernicke’s encephalopathy. Hypoglycaemia frequently occurs during intercurrent infection or during starvation and acidosis, requiring bicarbonate therapy. The most severe form, originally reported from France, progresses rapidly with evidence of liver damage, hyperammonaemia, hyperlysinaemia, and citrullinaemia.
This disorder is transmitted as an autosomal recessive trait. In severely affected patients with hyperammonaemia, pyruvate carboxylase protein and its mRNA are absent in the liver. A partially inactive variant enzyme is detectable in other patients.
Diagnosis and treatment
The condition is suspected when acidosis and neurological disease occur in infants, especially in the presence of hypoglycaemia. As discussed above in relation to lactic acidosis, specific diagnosis requires enzymatic assay in fibroblasts, which can also be used for carrier detection. Three main forms are recognized (see Wang and De Vivo, 2011): type A with and infantile-onset and mild to moderate lactic acidemia; normal lactate-to-pyruvate ratio despite acidemia; type B with increased lactate-to-pyruvate ratio; increased acetoacetate to 3-hydroxybutyrate ratio; elevated blood concentrations of citrulline, proline, lysine, and ammonia; low concentration of glutamine and type C, characterized by episodic metabolic acidosis with normal citrulline plasma concentrations and elevated lysine and proline plasma concentrations. Disorders of pyruvate metabolism may be mimicked biochemically by mitochondrial diseases and acquired deficiencies of thiamine or biotin. Although biotin therapy has been disappointing in pyruvate carboxylase deficiency, occasional responses to high-dose lipoic acid and thiamine treatment, which may stimulate pyruvate metabolism by the dehydrogenase complex, have been recorded. The ketogenic diet is contraindicated in pyruvate carboxylase deficiency.
Episodes of acidosis are treated with intravenous sodium bicarbonate, and glucose may be required for hypoglycaemia. The administration of glutamate and aspartate, which may act as a source of oxaloacetate, appear to have been beneficial in some patients. Avoiding metabolic stress due to starvation and sepsis is critical as well as frequent monitoring of lactate concentrations. Biotin supplementation should be given given as a cofactor to stabilize the mutant enzyme but is not usually effective. Anaplerotic therapy uses sources of energy and substrates for both the citric acid cycle and the electron transport chain for enhanced synthesis of ATP. Anapleurotic substrates include citrate supplementation, which can reduce the acidosis and supplies substrate for the Krebs’ cycle; aspartic acid supplements expedite the disposal of nitrogen as ammonia through the urea cycle but appears not to affect neurological function directly because it is unable to enter the brain. Triheptanoin, an odd-carbon triglyceride given orally, provides a source for acetyl-CoA and anapleurotic propionyl-CoA and dramatically improved hepatic failure and corrected all the biochemical disturbances in biotin-unresponsive pyruvate carboxylase deficiency type B. The compound supplies C5 ketone bodies that cross the blood-brain barrier. Evidence is scant and requires more experience but triheptanoin is the only available agent with the potential to improve brain metabolism in this disorder. In few desperqtely ill patients, orthotopic liver transplantation has reversed the biochemical abnormalities but its capacity to address all the neurological consequences of pyruvate carboxylase deficiency may be doubted.
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