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Inherited metabolic disease

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S. K. Sandhu, G. P. Sinha.Walsall Manor Hospital NHS Trust, West Midlands, UK

Background: Pompe’s disease is an autosomal recessive disorder in which a deficiency in the enzyme acid alpha-1,4-glucosidase (acid maltase) results in the intralysosomal accumulation of glycogen and the subsequent destruction of muscle tissue. Complete deficiency of this enzyme causes a rapidly progressive fatal cardiac and skeletal muscle disorder known as infantile Pompe’s disease. Partial deficiency leads to a milder late onset proximal myopathy with symptoms restricted to skeletal muscle.

Case Study: We present a family in which both father and son presented simultaneously with progressive muscle weakness. The son first presented to us with a failure to achieve major gross motor developmental milestones. He was able to walk independently at the age of 18 months, but had difficulty in standing from the sitting/lying position, climbing stairs, and in running. During a detailed neuromuscular assessment he was found to have a normal functional score of 40 despite having truncal weakness and a lordotic posture. He had numerous investigations of which the only abnormality was an elevated serum creatine kinase of 713 U/l. During this period his 34 year old father, who had a healthy active childhood, was also being investigated for proximal muscle myopathy. Over the past few years he had noticed an increasing difficulty in getting up from the squatting position. The father’s serum creatine kinase was also raised at 2088 U/l. All other routine blood tests were normal except an elevated lactate dehydrogenase level of 1177 IU/l. The father was then arranged to have a quadriceps muscle biopsy which revealed a “vacuolar myopathy with excess glycogen storage consistent with an inborn error of glycolytic metabolism such as acid maltase deficiency”. After these results both father and son were arranged to have skin biopsies. Culture of their fibroblasts confirmed that both father and son have low levels of the enzyme acid alpha-1,4-glucosidase. Subsequent DNA analysis has revealed that both father and son are homozygous for the 1437G>A mutation in the gene encoding this enzyme. The mother’s DNA shows heterozygosity for this nucleotide change. These results have had major implications in the genetic counselling of this multiply consanguineous family, especially as there is a possibility of successful enzyme replacement therapy in the near future.

Conclusion: The complete diagnosis of late onset Pompe’s disease is a lengthy procedure, especially as it usually presents with a proximal myopathy for which there is an exhaustive list of differentials. Five years after initial presentation our family is still being investigated. Currently further DNA analyses are underway to attempt the discovery of whether variable penetrance is the reason why the son has a much earlier age of onset of Pompe’s disease despite having the exact mutation as his father.


H. L. F. Coutts, J. H. Walter.Willink Biochemical Genetic Unit Royal Manchester Children’s Hospital, Manchester, UK

Background: Hyperammonaemia occurs with metabolic decompensation in patients with propionic acidaemia, especially in the neonatal period, and can result in permanent neurological damage. The cause of the increased ammonia is thought to be due to inhibition of carbamylphosphate synthase (CPS), the first enzyme of the urea cycle, by propionyl glutamate. It has been suggested that N-carbamylglutamate (N-CG), an activator of CPS may be effective in reducing hyperammonaemia in propionic acidaemia.

Case Study: An 11 day old baby with propionic acidaemia, born to consanguineous parents, presented with encephalopathy and was found to have a blood ammonia of 2000 μmol/l. An older sibling had died of propionic acidaemia but the parents had declined prenatal and immediate postnatal investigation. He was started on sodium benzoate, L-carnitine, glucose, and insulin. The ammonia decreased to 1680 μmol/l. While preparing for continuous veno-venous haemofiltration (CVVH) he received a single dose of N-carbamylglutamate 25 mg/kg by nasogastric tube. The ammonia rose over 2 hours to 2080 μmol/l. CVVH was commenced and his ammonia then decreased to 265 μmol/l over 9 hours. CVVH was continued for 22 hours. He was discharged home after 12 days on a low protein diet, l-carnitine, and metronidazole.

Discussion: A rapid reduction of blood ammonia is essential in order to reduce mortality and morbidity in patients with propionic acidaemia. Although CVVH is effective it is an invasive treatment not without significant risk such as haemorrhage and thrombosis. Clearly it would be beneficial to reduce ammonia levels by less invasive means or at least to attenuate the hyperammonaemia while preparing for CVVH. However, in this patient with propionic acidaemia and severe hyperammonaemia, there was no beneficial response to N-CG. It is not clear whether this was due to the severity of the hyperammonaemia, the fact that a relatively low dose of N-CG was used, or that treatment with N-CG is not effective in this disorder.


M. Galogavrou, S. E. Olpin, S. Clark, N. J. Manning, M. Downing, C. Hart, J. Watkinson, J. R. Bonham, M. J. Sharrard.Sheffield Children’s Hospital, Sheffield, UK

Background: CPT II deficiency is an autosomal recessive disorder of fatty acid oxidation with three basic phenotypes: late onset muscular, infantile/juvenile hepatic, and severe neonatal.

Case Study: A 1 year old boy born to unrelated parents presented with an episode of febrile generalised convulsions after a short illness. Growth and development were normal. He was found to have a blood sugar of 0.9 mmol/l and he responded to intravenous glucose. He is subsequently clinically normal. Initial investigations showed a hypoketosis and urinary organic acid analysis showed a marked dicarboxylic aciduria and large adipate suggesting a fatty acid oxidation disorder (FAOD). Low free plasma carnitine was detected (2.4 μmol/l). Blood spot C12 and C14 acylcarnitines were disproportionately high (0.48 μmol/l and 0.89 μmol/l, ref. <0.3) and indicated a long chain fatty oxidation disorder. His neonatal blood spot showed similar abnormalities. A long chain FAOD such as very long chain acyl-CoA dehydrogenase (VLCAD) deficiency was presumed. Cardiac USS and liver profile were normal. Skin biopsy was taken. Treatment was with a low fat diet supplemented with medium chain triglyceride and carnitine. On treatment blood spot acylcarnitines and urine dicarboxylic acids normalised. Fibroblast fatty acid oxidation studies showed reduced oxidation of palmitate, myristate, and oleate to 16%, 17%, and 19 % of the control means confirming the diagnosis of FAOD but excluding VLCAD. CPT II activity was reduced to 14% (fibroblast sonicated cell assay) and the diagnosis of CPT II deficiency was established.

Conclusion: This patient had a mild presentation of a type not previously reported with a mildly abnormal blood spot acylcarnitine profile. His case supports the importance of collecting skin biopsy to enable definite diagnosis.

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