Long-chain 3-hydroxyacyl–coenzyme A dehydrogenase deficiency with the G1528C mutation: Clinical presentation of thirteen patients

doi:10.1016/S0022-3476(97)70312-3

The Journal of Pediatrics

Volume 130, Issue 1, January 1997, Pages 67-76

https://doi.org/10.1016/S0022-3476(97)70312-3 Get rights and content

Abstract

Long-chain 3-hydroxyacyl—coenzyme A (CoA) dehydrogenase is one of three enzyme activities of the mitochondrial trifunctional protein. We report the clinical findings of 13 patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. At presentation the patients had had hypoglycemia, cardiomyopathy, muscle hypotonia, and hepatomegaly during the first 2 years of life. Seven patients had recurrent metabolic crises, and six patients had a steadily progressive course. Two patients had cholestatic liver disease, which is uncommon in β-oxidation defects. One patient had peripheral neuropathy, and six patients had retinopathy with focal pigmentary aggregations or retinal hypopigmentation. All patients were homozygous for the common mutation G1528C. However, the enoyl-CoA hydratase and 3-ketoacyl-CoA thiolase activities of the mitochondrial trifunctional protein were variably decreased in skin fibroblasts. Dicarboxylic aciduria was detected in 9 of 10 patients, and most patients had lactic acidosis, increased serum creatine kinase activities, and low serum carnitine concentration. Neuroradiologically there was bilateral periventricular or focal cortical lesions in three patients, and brain atrophy in one. Only one patient, who has had dietary treatment for 9 years, is alive at the age of 14 years; all others died before they were 2 years of age. Recognition of the clinical features of long-chain 3-hydroxyacyl-CoA deficiency is important for the early institution of dietary management, which may alter the otherwise invariably poor prognosis.

J Pediatr 1997;130:67-76

Section snippets

Patients

The diagnosis of LCHAD deficiency was made in 13 patients during the period from 1991 to 1995, in 12 cases post mortem. The diagnosis relied on the measurement of the activities of 3-hydroxyacyl-CoA dehydrogenase, enoyl-CoA hydratase, and 3-ketoacyl-CoA thiolase for long-chain fatty acids in cultured skin fibroblasts (nine patients) or on typical clinical features in a sibling with a verified diagnosis of the disease (four patients).

Enzyme analysis

The enzyme activities of the trifunctional protein were

Clinical presentation

Family history. The clinical features of the patients are shown in Table I.

. Clinical features of 13 patients with LCHAD deficiency

Empty Cell	Patient No. (sex)
Empty Cell	1 (F)	2 (M)	3 (F)	4 (M)	5 (M)	6 (F)
Age at onset	2 mo	3 mo	(3 days) 4 mo	(2 days) 1 mo	1 yr 9 mo	1 yr 5 mo
Age at death	3 mo	4 mo	9 mo	3 mo	1 yr 9 mo	14 yr (alive)
Pregnancy and delivery	GWk 40 + 4 BW 3000 gm	GWk 30 + 3 BW 1370 gm Preeclampsia, cesarean delivery	GWk 38 + 1 BW 3130 gm	GWk 36 + 5 BW 3140 gm	Normal	GWk 38 BW 2930 gm Geminus, preeclampsia

Neonatal period	Vomiting

DISCUSSION

The discovery that LCHAD activity resides in the mitochondrial trifunctional protein, which simultaneously contains two other enzyme activities, has caused some nosologic confusion, and the clinical presentation in the distinct forms of these disorders is not clearly characterized. Our series of 13 patients with LCHAD deficiency caused by the homozygous G1528C mutation allows a more precise delineation of the clinical features of one entity of the trifunctional protein deficiency.

The overall

Acknowledgements

We thank Professor Christina Raitta, MD, and Dr. Marjatta Lappi, MD, for their help in the ophthalmologic details. We are also grateful to Dr. Aimo Ruokonen for reassessing some of the analyses of urinary organic acids.

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Despite early start, and good compliance of the therapy, relatively high DHA supplementation, six of ten younger patients developed neuropathy, which suggest that polyneuropathy develops in LCHADD despite of current therapy. However, compared to previously reported patients7,8,10 the polyneuropathy is less severe, suggesting that the current therapy has slowed down the progression. Also the acylcarnitine levels remain elevated suggesting that diet is not optimal and more research is needed to evaluate in more detail the consistency of the diet.
The neonatal screening and early start of the dietary therapy have improved the outcome of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD). The acute symptoms of LCHADD are hypoketotic hypoglycemia, failure to thrive, hepatopathy and rhabdomyolysis. Long term complications are retinopathy and neuropathy. Speculated etiology of these long term complications are the accumulation and toxicity of hydroxylacylcarnitines and long-chain fatty acid metabolites or deficiency of essential fatty acids.
To study the possible development of polyneuropathy in LCHADD patients with current dietary regimen.
Development of polyneuropathy in 12 LCHADD patients with the homozygous common mutation c.G1528C was evaluated with electroneurography (ENG) studies. The ENG was done 1–12 times to each patient, between the ages of 3 and 40 years. Clinical data of the patients were collected from the patient records.
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^☆: Supported by the Arvo and Lea Ylppö Foundation.

^☆☆: Reprint requests: Tiina Tyni, MD, Children's Hospital, Stenbäckinkatu 11, FIN-00290 Helsinki, Finland.

^★: 9/21/76355

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Long-chain 3-hydroxyacyl–coenzyme A dehydrogenase deficiency with the G1528C mutation: Clinical presentation of thirteen patients☆,☆☆,★

Abstract

Section snippets

Patients

Enzyme analysis

Clinical presentation

DISCUSSION

Acknowledgements

Lancet

J Biol Chem

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Biochim Biophys Acta

Blood

J Pediatr

J Pediatr

Lancet

J Pediatr

J Pediatr

Two α subunit donor splice site mutations cause human trifunctional protein deficiency

J Clin Invest

Combined enzyme defect of mitochondrial fatty acid oxidation

J Clin Invest

Peripheral sensory-motor polyneuropathy, pigmentary retinopathy, and fatal cardiomyopathy in long-chain 3-hydroxy-acyl-CoA dehydrogenase deficiency

Eur J Pediatr

Long-chain 3-hydroxyacyl-coA dehydrogenase deficiency

Pediatr Res

β-oxidation enzymes in fibroblasts from patients with 3-hydroxydicarboxylic aciduria

Pediatr Res

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: high frequency of the G1528C mutation with no apparent correlation with the clinical phenotype

J Inher Metab Dis

Long-chain 3-hydroxyacyl-CoA dehydrogenase in leukocytes and chorionic villus fibroblasts: potential for pre- and postnatal diagnosis

J Inher Metab Dis

Long-chain 3-hydroxyacyl-CoA dehydrogenase in chorionic villi, fetal liver and fibroblasts and prenatal diagnosis of 3-hydroxyacyl-CoA dehydrogenase deficiency

J Inher Metab Dis