8 Various Organic Acidurias
Alberto Burlina, John Walter
8.1 Introduction
This chapter is concerned with the treatment the following disorders: 2-keto- glutarate dehydrogenase complex deficiency (2-ketoglutarate dehydrogenase deficiency and dihydrolipoamide S-succinyltransferse deficiency); fumarase de- ficiency; malonyl CoA decarboxylase deficiency; l-2-hydroxyglutaric aciduria;
d-2-hydroxyglutaric aciduria and aspartoacylase deficiency (Canavan disease) (see Nomenclature section).
2-Ketoglutarate dehydrogenase and fumarase deficiency are disorders in- volving enzymes of the Krebs cycle; malonyl CoA decarboxylase is responsible for the conversion of intramitochondrial malonyl-CoA to acetyl-CoA and plays an important role in fatty acid oxidation; no enzyme deficiencies have yet been found for either l-2-hydroxyglutaric aciduria or d-2-hydroxyglutaric aciduria;
aspartoacylase is a key enzyme within the central nervous system.
All these disorders are rare. In the section Clinical Features and Prognosis is a summary of the clinical presentation and prognosis of these disorders. The method of diagnosis and further details of the clinical presentation are de- scribed in the corresponding chapter of the Physicians Guide to the Laboratory Diagnosis of Metabolic Diseases.
94 Various Organic Acidurias 8.2 Nomenclature
No. Disorder (symbol) Definitions/comment Gene symbol OMIM No.
8.1 2-Ketoglutarate dehydrogenase deficiency, dihydrolipoamide S-succinyltransferse deficiency (2-ketoglutarate dehydrogenase complex deficiency, E1 and E2 components)
2-KGA (U) 5–1700 mmol/mol Creat OGDH
DLST
203740, 126063
8.2 Fumarase deficiency FA (U) > 20–3829 mmol/mol Creat FH 606812
8.3 Malonyl CoA decarboxylase deficiency
MA (U) 21–5440 mmol/mol Creat MLYCD,
MCD
248360 8.4 l-2-Hydroxyglutaric aciduria l-2-HGA (U) 226–4294 mmol/mol
Creat
236792 8.5 d-2-Hydroxyglutaric aciduria d-2-HGA (U) 676–7076 mmol/mol
Creat
600721 8.6 Aspartoacylase deficiency NAA (U) 61–9647 mmol/mol Creat ASPA 271900
8.3 Clinical Features and Prognosis
Disorder Clinical features Prognosis
8.1 2-Ketoglutarate dehydrogenase complex deficiency
(E1 and E2 components)
Variable: hypotonia, developmental-delay, pyra- midal and extrapyramidal dysfunction, spastic- ity, and hepatomegaly. E1 deficiency cause of the AR form of DOOR syndrome (deafness, onycho- osteodystrophy, dystrophic thumbs, sensorineu- ral deafness; Surendran et al. 2002)
Variable
8.2 Fumarase deficiency Variable encephalopathy Usually fatal in infancy 8.3 Malonyl CoA decarboxy-
lase deficiency
Developmental delay, seizures, vomiting, hypo- glycemia, hypertrophic cardiomyopathy (Santer et al. 2003)
Variable
8.4 l-2-Hydroxyglutaric aciduria
Developmental and motor delay, seizures, cere- bellar ataxia, migraine, macrocephaly, leukoen- cephalopathy, spinal canal stenosis (Kossoff et al.
2001; Warmuth-Metz et al. 2000; Sztriha et al.
2002)
Usually slowly progressive with survival into Adult- hood
8.5 d-2-Hydroxyglutaric aciduria
Mild infantile form: epilepsy, hypotonia, and psychomotor retardation, facial dysmorphism.
Severe neonatal form: as above plus absence corpus callosum, intracranial haemorrhage, episodic vomiting, cardiomyopathy, intractable seizures, inspiratory stridor, and apneas (Kwong et al. 2002; Wang et al. 2003). Intermediate form also described (Clarke et al. 2003)
severe form: death in in- fancy, other forms: variable
8.6 Aspartoacylase deficiency
Macrocephaly, psychomotor regression, optic at- rophy,seizures (Rapin 2000)
Often death in childhood or teens; severe disability
Treatment 95 8.4 Treatment
With the exception of malonyl-CoA decarboxylase deficiency, there are no treatments that have been shown to modify the natural history of these dis- orders. Clinical variability has been described in all of these disorders except for Canavan disease, which is often fatal within early childhood, although survival in a vegetative state or near-vegetative state may extend to the second decade (Rapin 2000). Each patient must be assessed on an individual basis. Treatment will be primarily supportive and for complications of the conditions that may arise. Knowledge of the natural history is important in order to anticipate such problems. Care for affected families includes genetic advice (see Follow- up/Monitoring section).
For patients with malonyl-CoA decarboxylase deficiency, a low-fat, high- carbohydrate diet has been reported to reduce the excretion of malonic acid and the risk from hypoglycemia and carnitine supplementation to prevent the development of cardiac decompensation (Haan et al. 1986; Matalon et al. 1993;
Krawinkel et al.1994; Yano et al.1997; Wightman et al. 2003; Santer et al. 2003).
However, less than 20 patients have been reported in the literature and, despite such treatment, the outcome appears variable.
Disorder Specific treatment
8.1 2-Ketoglutarate
dehydrogenase complex deficiency
Low CHO; bicarbonate
8.2 Fumarase deficiency None 8.3 Malonyl CoA decarboxy-
lase deficiency
High-carbohydrate, low-fat diet and carnitine, but response very variable. Systemic symptoms and cardiomyopathy often improve but not de- velopmental delay
8.4 l-2-Hydroxyglutaric aciduria
None (spinal decompression for spinal cord stenosis).
8.5 d-2-Hydroxyglutaric aciduria
None 8.6 Aspartoacylase
deficiency
None
8.5 Alternative Therapies/Experimental Trials
There is no established therapy for preventing the neurological damage in these disorders. Recently the use of topiramate has been suggested in the treatment of Canavan disease and l-2-OH glutaric aciduria, but the results are still too preliminary to define as a new treatment (Topcu et al. 2003).
Several studies using viral and nonviral gene delivery gene systems have been carried out in an attempt to correct the enzyme deficiency in Canavan
96 References
disease. Canavan disease may be a reasonable target for an ASPA gene transfer strategy, since it is a single-gene defect and it is possible that the neuropathology could be reversed by reduction of enhanced brain N-acetylaspartic acid (NAA) levels (Kirmani et al. 2002). Although different approaches have been reported, including attempts in humans (nonviral gene delivery of human ASPA in an AAV plasmid in two children with Canavan disease, one with a homozygous mutation and the other with a heterozygous mutation; Leone et al. 2000; Matalon et al. 2003), an efficacious therapy has yet to be reached.
Disorder Alternative therapies/
experimental trials 8.1 2-Ketoglutarate dehydrogenase complex
deficiency
None
8.2 Fumarase deficiency None
8.3 Malonyl CoA decarboxylase deficiency None 8.4 l-2-Hydroxyglutaric aciduria None 8.5 d-2-Hydroxyglutaric aciduria None
8.6 Aspartoacylase deficiency Topiramate; gene therapy
8.6 Follow-up/Monitoring
Disorder Follow-up/monitoring
8.1 2-Ketoglutarate dehydrogenase deficiency Supportive; acid/base status, blood lactate
8.2 Fumarase deficiency Supportive; acid/base status, blood lactate
8.3 Malonyl CoA decarboxylase deficiency Carnitine status, acid base status, urine organic acids
8.4 l-2-Hydroxyglutaric aciduria Supportive 8.5 d-2-Hydroxyglutaric aciduria Supportive
8.6 Aspartoacylase deficiency Supportive
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