Deafness, Dystonia, And Cerebral Hypomyelination

A number sign (#) is used with this entry because deafness, dystonia, and cerebral hypomyelination (DDCH) is caused by hemizygous mutation in the BCAP31 gene (300398) on chromosome Xq28.

Description

Deafness, dystonia, and cerebral hypomyelination is an X-linked recessive mental retardation syndrome characterized by almost no psychomotor development, dysmorphic facial features, sensorineural deafness, dystonia, pyramidal signs, and hypomyelination on brain imaging (summary by Cacciagli et al., 2013).

Clinical Features

Cacciagli et al. (2013) reported 7 males from 3 unrelated families with severe syndromic X-linked mental retardation apparent at birth or in the first years of life and almost no apparent motor or cognitive development. The oldest patients died at 13 and 24 years of age. The other patients died suddenly or during a febrile illness between 7 months and 3 years of age. One patient was alive as a teenager. All patients had dysmorphic features, including microcephaly and congenital strabismus, failure to thrive, deafness, early-onset dystonia, and pyramidal signs with quadriplegia. Three patients had seizures and 2 had optic atrophy. Brain MRI performed in 3 patients showed periventricular or diffuse hypomyelination with variable cerebral or cerebellar atrophy. Four patients showed transiently increased liver enzymes during febrile illness, but liver ultrasound did not show any abnormalities.

Inheritance

The transmission pattern of DDCH in the families reported by Cacciagli et al. (2013) was consistent with X-linked recessive inheritance. Carrier females were unaffected.

Cytogenetics

Corzo et al. (2002) reported 3 newborn males with profound neonatal hypotonia, failure to thrive, and cholestatic liver disease confirmed by liver biopsy. Two of the patients developed seizures at age 2 months; the third did not have seizures but experienced frequent episodes of opisthotonos and bruxism. Sensorineural deafness was present in 2 of the patients and cataract in 1. All 3 patients died within the first year of life. At autopsy, 1 patient had small, fibrotic adrenal glands and 1 had delayed myelination in the brain. Two of the patients were French Canadian and 1 Vietnamese. Biochemical studies showed increased levels of plasma very long chain fatty acids and normal peroxisomes, consistent with a peroxisomal single-enzyme deficiency. Patient fibroblasts showed lack of the adrenoleukodystrophy protein, and molecular studies identified a hemizygous deletion that extended into the promoter region of the ABCD1 gene (300371) and the neighboring gene, BCAP31, in each patient. The deletions all had different breakpoints. Two of the 3 asymptomatic mothers were heterozygous carriers. Corzo et al. (2002) noted that the very early onset of neurologic features and the liver disease were unusual findings in classic ALD (300100) due to ABCD1 mutations.

Osaka et al. (2012) reported a 6-year-old Japanese boy who presented at age 8 months with hypertonia, hyperreflexia, extensor plantar responses, and dystonia. He could not hold his head or follow an object with his eyes. Laboratory studies showed normal very long chain fatty acids and recurrent elevation of liver enzymes during illness. The patient also had sensorineural deafness. Brain MRI showed delayed myelination with decreased cerebral white matter volume, thin corpus callosum, and increased T2-weighted signals in the globus pallidus. The child developed status epilepticus at age 4 years. Brain magnetic resonance spectroscopy showed a deficient creatine peak, and there was a severe decrease in creatine uptake in patient fibroblasts. Molecular studies identified a de novo heterozygous 19-kb deletion of chromosome Xq28 including exons 5 to 13 of the SLC6A8 gene (300036) and exons 5 to 8 of the BCAP31 gene. Loss of SLC6A8 was consistent with cerebral creatine deficiency syndrome-1 (CCDS1; 300352). Western blot analysis of patient cells showed lack of a normal BCAP31 protein, and Osaka et al. (2012) suggested that the lack of BCAP31 was related to the liver abnormalities and sensorineural deafness observed in their patient.

Molecular Genetics

In 7 affected males from 3 unrelated families with an X-linked mental retardation syndrome characterized by deafness, dystonia, and central hypomyelination, Cacciagli et al. (2013) identified 3 different hemizygous mutations in the BCAP31 gene (300398.0001-300398.0003). All mutations caused a loss of protein function. The mutation in the first family was found by X-chromosome exome analysis, and the other 2 mutations were found by screening the BCAP31 gene in 29 male probands with severe intellectual disability, dystonia, and deafness. Patient fibroblasts showed swollen endoplasmic reticulum lumens and abnormal Golgi morphology. The cells contained large cytoplasmic vesicles partially filled with electron-dense inclusions that suggested impaired ER-to-Golgi exchanges. However, there was not a massive accumulation of misfolded proteins, abnormal activation of the unfolded protein response, or apoptosis. The findings linked intracellular protein trafficking to severe congenital brain dysfunction, including defective myelination, and deafness.