Cerebellar Ataxia, Mental Retardation, And Dysequilibrium Syndrome 2

A number sign (#) is used with this entry because of evidence that cerebellar ataxia, mental retardation, and dysequilibrium syndrome-2 (CAMRQ2) is caused by homozygous mutation in the WDR81 gene (614218) on chromosome 17p.

Description

Cerebellar ataxia, mental retardation, and dysequilibrium syndrome (CAMRQ) is a genetically heterogeneous disorder characterized by congenital cerebellar ataxia and mental retardation (summary by Gulsuner et al., 2011).

For a discussion of genetic heterogeneity of CAMRQ, see CAMRQ1 (224050).

Clinical Features

Turkmen et al. (2006) reported a consanguineous Turkish family of Kurdish origin in which 5 sibs had cerebellar hypoplasia, mental retardation, and an inability to walk bipedally, resulting in quadrupedal locomotion as a functional adaptation. An affected brother and sister were bipedal but had similar neurologic features and a lesser degree of cognitive impairment. One of the quadrupedal sibs died at age 26 years of unknown causes. Detailed examination of the 28-year-old male proband showed moderate thoracic kyphosis, short stature, cerebellar ataxia, dysarthria, dysmetria, and dysdiadochokinesia without pyramidal signs. He preferred to walk on his extremities with entire hands and feet touching the ground (palmigrade walking) and fully stretched knee and elbow joints. All 4 affected individuals moved about freely and participated most of the time in the family's daily work in the fields. They could understand and communicate basic words, but cognitive abilities were severely impaired. Brain MRI of affected individuals showed hypogenesis and midline clefting of the cerebellar vermis. In all cases the superior half of the vermis was formed, whereas the inferior section was not. The dentate nucleus was atrophic. Other findings included generalized brain atrophy and mild hypoplasia of the corpus callosum. Cortical dysplasia, lissencephaly, and gray matter heterotopia were not observed. Individuals who demonstrated quadrupedal locomotion did so effectively and without discomfort. As they moved, their knee and elbow joints showed almost no flexion, and their hands touched the ground mainly on their palms, distinct from knuckle walking of great apes.

Tan (2006) provided a report of the same family. He noted that the affected individuals demonstrated diagonal walking seen in many animals, such as dogs, horses, and chimpanzees. Tan (2006) suggested that this syndrome may represent a live model for human evolution from quadrupedal to bipedal gait.

Gulsuner et al. (2011) reported detailed neuroradiologic studies of the patients reported by Turkmen et al. (2006). Brain MRI of affected individuals showed morphologic abnormalities in the cerebellum and corpus callosum, in particular atrophy of superior, middle, and inferior peduncles of the cerebellum. Structural MRI showed additional morphometric abnormalities in several cortical areas, including the corpus callosum, precentral gyrus, and several Brodmann areas.

Garcias and Martino Roth (2007) reported 4 Brazilian sibs, 2 males and 2 females, born of consanguineous parents, with a clinically homogeneous syndrome in which the predominant characteristic was a quadrupedal gait. All had a normal neonatal period but did not learn to crawl normally on 4 limbs. When they learned to 'walk,' they assumed a quadrupedal position leaning on the hands and feet with erect lower limbs. Radiographic exams showed no osteoarticular changes that could justify the quadrupedal gait. All sibs had mental retardation with absent speech, short stature, coarse facial features, hirsutism, strabismus, wide and short nape of the neck, and small hands and feet. Secondary sexual characteristics were normal, except that the males had small penis. One sib had convulsions around puberty.

Komara et al. (2016) reported 2 sisters, born of consanguineous parents of Yemeni descent, with CAMRQ2. The girls were 3 and 7 years old, respectively. Both had global developmental delay followed by evidence of gait ataxia; 1 sister had intention tremor. Brain imaging of both girls showed cerebellar hypoplasia. The younger sister had profound sensorineural hearing loss, most likely due to a mutation in another gene (see MOLECULAR GENETICS).

Etiology of Quadrupedal Locomotion

Ozcelik et al. (2008) maintained that quadrupedal locomotion in the affected individuals results from abnormal function of brain structures that are critical for gait. Humphrey et al. (2008) concluded that the tendency toward quadrupedal locomotion in affected individuals is an adaptive and effective compensation for problems with balance caused by congenital cerebellar hypoplasia. Thus, the unusual gait could be attributed to the local cultural environment. Herz et al. (2008) also concluded that quadrupedal locomotion is more likely an adaptation to severe truncal ataxia, resulting from a combination of uneven, rough surfaces in rural areas, imitation of affected sibs, and lack of supportive therapy. Ozcelik et al. (2008) responded and defended their position.

Inheritance

The transmission pattern of CAMRQ2 in the family reported by Turkmen et al. (2006) was consistent with autosomal recessive inheritance.

Mapping

By genomewide linkage analysis of the affected Turkish family, Turkmen et al. (2006) identified a candidate disease locus on chromosome 17p between markers D17S1866 and D17S690 (peak multipoint lod score of 5.37 was calculated between D17S831 and D17S1298).

Ozcelik et al. (2008) confirmed linkage to chromosome 17p13 in the family previously reported by Turkmen et al. (2006). They reported 1 unrelated Turkish family that showed no evidence of linkage to 17p13 and 9p24.

Molecular Genetics

In affected members of a consanguineous Turkish family with autosomal recessive cerebellar ataxia, mental retardation, and dysequilibrium syndrome-2 (Turkmen et al., 2006), Gulsuner et al. (2011) identified a homozygous mutation in the WDR81 gene (P856L; 614218.0001). Homozygosity for the mutation segregated with the phenotype. The mutation occurred in a highly conserved residue, and was not found in 549 controls. The mutation was found by targeted sequencing of the candidate disease region identified by linkage analysis. WDR81 was expressed in the cerebellum and corpus callosum.

Alazami et al. (2015) identified a homozygous missense variant in the WDR81 gene (G282E) in a patient from a consanguineous family with CAMRQ2. The phenotype was noted to be neonatal death due to severe brain malformation, including hydranencephaly and severe cerebellar hypoplasia. Additional clinical details and family history were not provided. The proband was part of a large cohort of 143 multiplex consanguineous families with various neurodevelopmental disorders who underwent whole-exome sequencing. Functional studies of the WDR81 variant were not performed.

In 2 sisters, born of consanguineous parents of Yemeni origin, with CAMRQ2, Komara et al. (2016) identified a homozygous truncating mutation in the WDR81 gene (R1333X; 614218.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. One of the patients, who also had hearing loss, had a homozygous missense variant (R158W) in the LHFPL5 gene (609427), which is responsible for autosomal recessive deafness-67 (DFNB67; 610265).