D-bifunctional Protein Deficiency: A Case Report of a Turkish Child.

Sir,

D-bifunctional protein deficiency (D-BP) is a very rare autosomal recessive disorder of peroxisomes caused by mutation of HSD17B4 (5q23.1) gene.[1] The HSD17B4 product of D-BP is a multifunctional enzyme which catalyzes the second (enoyl-CoA hydratase) and third steps (3-hydroxyacyl-CoA dehydrogenase) of peroxisomal fatty acid β-oxidation.[2] D-BP has a dehydrogenase, a hydratase, and a sterol carrier protein-2 (SCP2) domains. Prototypical patients with D-BP deficiency show muscular hypotonia, poor sucking, craniofacial anomalies, hepatomegaly, and seizures beginning from the neonatal period and leading to the death of the patient by the age of 2 years.[3] To date, only a few patients with D-BP deficiency have been described in the literature.[3456] Here, we report a Turkish girl with D-BP deficiency, who presented with drug-resistant seizures, dysmorphism, and psychomotor retardation.

Our case was a 4-year-old girl admitted to our hospital with drug-resistant seizures and severely delayed psychomotor development. At the 1st month of life, she developed tonic seizures, which were treated with phenobarbital successfully. At the age of 12 months, both tonic–clonic and focal seizures occurred once or twice a week and valproic acid and levetiracetam initiated. However, antiepileptic drugs had been revised frequently due to intractable seizures.

She was born to healthy consanguineous parents after an uncomplicated pregnancy at the 32th week of gestation via vaginal delivery. Her birth weight was 1500 g, birth length was 40 cm, and head circumference was 31 cm. She was hospitalized in a Neonatal Intensive Care Unit with hypotonia and feeding problems for 26 days. The family history was unremarkable for a neurological or an inherited metabolic disease. There was no history of a teratogenic agent exposure during pregnancy. On physical examination at admission, she had severe growth retardation, malnutrition, hypotonia, bilateral sensorineural deafness, and dysmorphic features such as broad forehead, high-arched palate, low-set ears, flat nasal bridge, and micrognathia. She could not say any meaningful words and could only sit without support. Laboratory evaluation revealed normal liver and renal function tests and thyroid hormone levels. Metabolic investigations including serum quantitative aminoacid levels and acylcarnitine profile, blood lactate and pyruvate levels and their ratio, very long-chain fatty acid (VLCFA), phytanic and pristanic acid levels, serum ammonia, and urine organic acid analysis were totally normal. The Stanford–Binet Intelligence Scale was compatible with severe psychomotor retardation. Echocardiography and abdominal ultrasonography revealed no abnormality. Cerebral magnetic resonance imaging (MRI) pointed out bilateral symmetrical hyperintense lesions in the posterior periventricular white matter [Figure 1]. Electroencephalography showed abnormal background activity and multifocal epileptic discharges. As all the metabolic investigations were normal, MRI did not indicate a specific diagnosis, the family history was suspicious for an inherited neurometabolic disease, and hence whole-exome sequencing analysis was performed. Surprisingly, a compound heterozygous mutation c.11C>G (p. Pro4Arg) and c.1976G>A (p. Arg659His) was found in the HSD17B4 gene. The mother was heterozygous for the mutation c.11C>G (p. Pro4Arg) and the father was heterozygous for the mutation c.1976G>A (p. Arg659His).

Figure 1

Cerebral magnetic resonance imaging showed bilateral symmetrical hyperintense lesions in the posterior periventricular white matter

D-BP deficiency is a very rare inherited metabolic disease with an estimated prevalence of 1:100,000.[1] D-BP has a dehydrogenase, a hydratase, and a SCP2 domain, and the deficiencies of these enzymes lead to four different subtypes of the disease. Type I is caused by the deficiencies of both dehydrogenase and hydratase activities of the D-BP, whereas Type II and Type III are caused by the deficiencies of hydratase and dehydrogenase enzymes, respectively.[5] Recently, a new form, Type IV, is proposed to describe the mildly affected patients with compound heterozygous mutations affecting both the dehydrogenase and hydratase activities.[345678] All the types are inherited in an autosomal recessive manner. The onset of symptoms of D-BP deficiency is usually in the neonatal period. Survival until late childhood is rare and generally it is fatal by the age of 2 years.[4] In a case series report of 126 patients with DBP deficiency diagnosed by D-BP activity measurements in fibroblasts, virtually all patients presented with neonatal hypotonia (98%) and seizures (93%) within the 1st month of life. Almost none of the patients acquired any psychomotor development, and the few patients who achieved some limited skills showed progressive loss of motor achievements. Detailed information about five patients with prolonged survival (>7.5 years) demonstrated that seizures were controlled with antiepileptic treatment in three patients and various types of seizures were poorly controlled in one patient. Only one patient had no seizures.[9] Nascimento et al. reported a case of D-BP deficiency with neonatal onset of seizures and hypotonia.[4] Buoni et al.[10] reported a case of D-BP deficiency with a peculiar epileptic phenotype defined as West syndrome with a modified hypsarrhythmic pattern and drug-resistant asymmetric spasms. Our patient was admitted to the hospital with typical clinical abnormalities described for D-BP deficiency, including neonatal hypotonia, seizures, dysmorphism, and developmental delay. Her tonic seizures showed a progression to resistant epilepsy in time. However, there were a few cases with milder clinical presentations in the literature.[7]

Biochemically, D-BP deficiency is characterized by increased plasma levels of VLCFA, di- and trihydroxycholestanoic acid, and pristanic acid.[2] Soorani-Lunsing et al.[11] reported a milder case of D-BP deficiency with normal levels of VLCFAs. Although the clinic is severe, VLCFA levels were normal in our case.

Common neuroimaging findings seen in D-BP deficiency are delayed myelination and demyelination of white matter, germinolytic cysts, and polymicrogyria of cerebral cortex. Interestingly, Mizumoto et al.[7] reported a patient without any abnormal finding on cerebral MRI. We demonstrated bilateral symmetrical hyperintense lesions in the posterior periventricular white matter in cerebral MRI.

In conclusion, although it is a rare neurometabolic disease, D-BP deficiency should be in the differential diagnosis of resistant epilepsy, neonatal hypotonia, and developmental delay. The interesting feature of our case was the normal levels of VLCFA despite the severe neurological involvement.

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Conflicts of interest

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