Microhydranencephaly

A number sign (#) is used with this entry because of evidence that microhydranencephaly (MHAC) is caused by homozygous mutation in the NDE1 gene (609449) on chromosome 16p13. One such family has been reported.

Mutation in the NDE1 gene can also cause lissencephaly-4 (LIS4; 614019).

Description

Microhydranencephaly (MHAC) is a severe neurodevelopmental defect characterized by extreme microcephaly, profound motor and mental retardation, spasticity, and incomplete cerebral formation. Radiologic studies show gross dilation of the ventricles resulting from the absence of cerebral hemispheres or severe delay in their development, as well as hypoplasia of the corpus callosum, cerebellum, and brainstem (summary by Guven et al., 2012).

Clinical Features

Kavaslar et al. (2000) reported a large consanguineous Anatolian (Turkish) family with children who had the unusual association of microcephaly and hydranencephaly. In addition, the affected children had severe mental and motor retardation, very small body size, and very small occipitofrontal circumference (OFC). The youngest patient, 4.5 years of age at the time of study, had a height corresponding to a sex mean of 7 months, weight to 1 month, and OFC to prenatal. Guven et al. (2012) reported follow-up of 2 surviving affected female cousins from the family reported by Kavaslar et al. (2000). The patients were 17 and 19 years of age, respectively. Both had thin bones, prominent nasal bridges, poor overall growth, and severe microcephaly (-11.1 and -7.8 SD, respectively). They had severe mental and motor retardation, could sit with support, did not have real eye contact, and had poor social interaction. Neurologic examination showed atrophic optic fundi, poor head control, automutilation of hands, tetraparesis, contractures of the knees, and generalized muscle atrophy. Brain MRI showed residues of cerebral cortical regions, but frontal lobes and the corpus callosum could not be distinguished. The cerebellum, vermis, and brainstem were hypoplastic. Pachygyria was also apparent in 1 patient. Both had notable scalp rugae.

Alexander et al. (1995) reported 2 female sibs with fetal brain disruption sequence. Clinical findings included large size at birth with a disproportionately small head circumference and scalp rugae. The degree of microcephaly became more marked with time. Cranial CT scan in both infants revealed gross dilation of the ventricles, almost complete absence of the cerebral hemispheres with a well-formed falx, and a small cerebellum. Elevated semiquantitative mucopolysaccharide levels were consistently obtained from both children, and high resolution electrophoresis revealed an unidentified metabolite and a pattern not consistent with any known mucopolysaccharidosis. Alexander et al. (1995) proposed that accumulation of a neurotoxic metabolite might be responsible for the disease phenotype.

Schram et al. (2004) reported 2 sibships with fetal brain degeneration resembling fetal brain disruption sequence: 2 brothers in a Hindu family from Suriname, and a Dutch brother and sister. All of the children had low birth weight, microcephaly, overlapping sutures, and scalp rugae. CT scans of their brains showed severely underdeveloped cerebral hemispheres surrounded by a large amount of cerebrospinal fluid. The authors noted that true hydranencephaly was not present in these cases, but questioned whether a strict delineation between hydranencephaly and fetal brain disruption sequence was justified. Schram et al. (2004) also commented that in cases of sib recurrence, the term 'fetal brain disruption sequence' should be avoided since a disruption sequence indicates an exogenous, sporadic cause of the disorder.

Inheritance

The transmission pattern of MHAC in the family reported by Kavaslar et al. (2000) was consistent with autosomal recessive inheritance.

Mapping

By use of homozygosity mapping (Lander and Botstein, 1987) in a single large consanguineous Anatolian (Turkish) family segregating for microhydranencephaly, Kavaslar et al. (2000) showed genetic linkage between the disorder and markers on chromosome 16p13.3-p12.1.

Molecular Genetics

In 2 cousins, born of consanguineous Turkish parents, with microhydranencephaly (Kavaslar et al., 2000), Guven et al. (2012) identified a homozygous intragenic deletion in the NDE1 gene (609449.0004). The mutation was predicted to result in a completely null allele, but functional studies were not performed. Guven et al. (2012) noted that the MHAC phenotype is more severe than that observed in patients with LIS4 (614019), thus expanding the spectrum of clinical features associated with NDE1 mutations.