Cerebellar Ataxia, Mental Retardation, And Dysequilibrium Syndrome 1

A number sign (#) is used with this entry because cerebellar ataxia, mental retardation, and dysequilibrium syndrome (CAMRQ1) is caused by homozygous mutation in the VLDLR gene (192977), which encodes the very low density lipoprotein receptor, on chromosome 9p24.

Description

This form of autosomal recessive cerebellar ataxia is characterized by congenital onset of nonprogressive cerebellar ataxia, disturbed equilibrium, and mental retardation, associated with cerebellar hypoplasia (Schurig et al., 1981; Glass et al., 2005).

Genetic Heterogeneity of CAMRQ

CAMRQ is a genetically heterogeneous disorder. See also CAMRQ2 (610185), caused by mutation in the WDR81 gene (614218) on chromosome 17p; CAMRQ3 (613227), caused by mutation in the CA8 gene (114815) on chromosome 8q11; and CAMRQ4 (615268), caused by mutation in the ATP8A2 gene (605870) on chromosome 13q12.

Clinical Features

Schurig et al. (1981) reported an autosomal recessive disorder characterized by nonprogressive congenital cerebellar ataxia with mental retardation in 11 patients among the Dariusleut Hutterites of Alberta. Delayed motor development and hypotonia were noted during the first year of life. None walked before age 3 years, and all pushed a 4-wheel appliance for support. They had mental retardation with virtually no language development. Consistent signs were unsteady, broadly based gait and stance, exaggerated deep tendon reflexes mainly in the lower limbs, and short stature. Nystagmus was not present, but some had strabismus. Three had intention tremor. One patient had seizures and another had cataracts. Computerized axial tomography showed cerebellar atrophy. Schurig et al. (1981) noted the phenotypic similarities to the cases reported by Sanner (1973), who reported affected individuals born of consanguineous parents in Sweden, and those of Norman (1940), who described patients with nonprogressive congenital cerebellar ataxia and mental retardation associated with cerebellar hypoplasia and loss of granule cells (SCAR2; 213200). Pallister and Opitz (1985) observed a similar disorder in the Dariusleut Hutterites of Montana.

Glass et al. (2005) reported follow-up of the phenotype observed in Canadian Hutterites as reported by Schurig et al. (1981). Twelve affected individuals who belonged to 1 large pedigree were examined. All patients had significant global delay noted in infancy. All had delayed motor development and pes planus, and none achieved independent walking before age 6 years. All had cerebellar findings, including dysarthria, truncal ataxia, gait ataxia, gaze-evoked nystagmus, and mild intention tremor. Neuroimaging showed hypoplasia of the inferior portion of the cerebellum and small brainstems, particularly the pons. The gyration of the cerebral hemispheres ranged from normal to mild simplification, and there was mild cortical thickening. There was no apparent progression in the MRI changes or disease course. Five patients had seizures.

Tan (2008) reported a consanguineous Turkish family from a village in Canakkale in which 3 individuals had mental retardation, lack of speech development, and walked on all 4 extremities. Brain MRI showed cerebellar and vermal hypoplasia with a flattened cerebral cortex. The individuals could stand upright and even walk bipedally, despite severe ataxia, but they walked with a quadrupedal gait.

Tan et al. (2008) reported another large family from southern Turkey in which 6 individuals had severe mental impairment and walked on all four extremities. Brain MRI showed absence of inferior portions of the cerebellum and vermis. One affected male exhibited 3 walking patterns at the same time: quadrupedal, tiptoe, and scissor walking. Another male showed quadrupedal locomotion and toe walking.

Turkmen et al. (2008) reported a family from Turkey in which 3 individuals had mental retardation, cerebellar hypoplasia, and quadrupedal locomotion associated with a homozygous deletion in the VLDLR gene (192977.0003). The authors postulated that although the precondition for quadrupedal locomotion is cerebellar hypoplasia and ataxia, the locomotion trait is most likely a behavioral phenotype depending on special environmental influences during child development.

Moheb et al. (2008) reported a consanguineous Iranian family in which 8 individuals had moderate to severe mental retardation, disturbed equilibrium, cerebellar ataxia, strabismus, and short stature associated with a homozygous truncating mutation in the VLDLR gene (R448X; 192977.0004). Affected individuals had either no speech at all or spoke only a few words. Motor development was retarded: they were able to sit independently between the ages of 12 and 24 months, but no patient could walk independently. No dysmorphic features or seizures were present, and brain imaging was not performed.

Kolb et al. (2010) reported a consanguineous Turkish family in which 2 sibs had delayed psychomotor development with speech delay, severely ataxic bipedal gait, dysarthria, dysmetria, dysdiadochokinesis, and hyperreflexia. Brain MRI showed cerebellar atrophy and predominantly frontal pachygyria. Homozygosity mapping followed by copy number variation analysis identified a homozygous 21-kb deletion in the VLDLR gene encompassing exons 2, 3, 4, and parts of exons 1 and 5 (chr9:2,612,148-2,633,338). Kolb et al. (2010) noted that the majority of patients with VLDLR mutations are able to use bipedal gait, suggesting that quadrupedal locomotion observed in some patients reflects an environmental adaptation.

Dixon-Salazar et al. (2012) reported 2 sibs, born of consanguineous Turkish parents, with congenital cerebellar ataxia and mental retardation. The patients had microcephaly, nystagmus, mild spasticity, arachnodactyly, and pontocerebellar hypoplasia on brain imaging. The patients were initially reported as having pontocerebellar hypoplasia (Dilber et al., 2002), but exome sequencing identified a mutation in the VLDLR gene (192977.0005), yielding the correct diagnosis.

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. They suggested the designation 'DES-VLDLR.' Ozcelik et al. (2008) defended their position.

Diagnosis

Differential Diagnosis

Quarrell and Hughes (1988) noted that since postnatal cataract had been described in rare affected individuals (Sanner, 1973; Schurig et al., 1981), Marinesco-Sjogren syndrome (MSS; 248800) should be considered in the differential diagnosis. A differentiating feature is elevated creatine kinase and progressive myopathy in MSS but not in DES. Baraitser (1993) referred to a pair of sibs with a clinical picture that would fit with a diagnosis of 'ataxic cerebral palsy'; progression of the ataxia was so slight that the correct diagnosis of carbohydrate-deficient glycoprotein syndrome (212065) was missed.

Mapping

Boycott et al. (2005) used an identity-by-descent mapping approach in 8 patients from 3 interrelated Hutterite families to localize the gene for this syndrome to 9p24. Haplotype analysis identified familial and ancestral recombination events and refined the minimal region of a 2-Mb interval between markers D9S129 and D9S1871.

By genomewide linkage analysis of 2 Turkish families with cerebellar atrophy and quadrupedal locomotion (Tan, 2008; Tan et al., 2008), Ozcelik et al. (2008) found significant linkage (lod scores greater than 3.0) to a 1.032-Mb region on chromosome 9p24.

Molecular Genetics

In affected individuals of 3 Hutterite families with DES, Boycott et al. (2005) detected a 199-kb homozygous deletion encompassing the entire VLDLR gene (192977.0001). VLDLR is part of the reelin (RELN; 600514) signaling pathway, which guides neuroblast migration in the cerebral cortex and cerebellum. This condition appeared to represent the first example of a malformation syndrome due to a defect in a human lipoprotein receptor and the second human disease associated with a reelin pathway defect. The other is a syndrome of autosomal recessive lissencephaly with cerebellar hypoplasia (257320) due to mutation in the RELN gene.

In affected members of 2 unrelated Turkish families with cerebellar hypoplasia, mental retardation, and quadrupedal locomotion, (Tan, 2008; Tan et al., 2008), Ozcelik et al. (2008) identified 2 different homozygous mutations in the VLDLR gene (192977.0002 and 192977.0003, respectively).

In 2 sibs, born of consanguineous Turkish parents, with congenital cerebellar ataxia and mental retardation, Dixon-Salazar et al. (2012) identified a homozygous truncating mutation in the VLDLR gene (192977.0005). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in 200 controls.

Population Genetics

Ali et al. (2012) identified a homozygous mutation in the VLDLR gene (C706F; 192977.0006) in 5 patients from 2 apparently unrelated Omani families with CAMRQ1. Haplotype analysis indicated a founder effect. The patients had classic features of the disorder, including delayed psychomotor development, hypotonia, mental retardation, lack of speech development, gait and truncal ataxia, cerebellar hypoplasia, and simplified cortical gyri.

Nomenclature

This disorder was originally called the 'dysequilibrium syndrome,' a term given by Hagberg et al. (1972) and Sanner (1973) to a form of ataxic cerebral palsy characterized by a nonprogressive variety of congenital abnormalities, including incoordination of voluntary movements, unsteady gait, and mental retardation. Affected individuals had disturbed equilibrium with severely retarded motor development.

Following demonstration of the defect in VLDLR in the Hutterite form of cerebellar hypoplasia, Boycott et al. (2005) proposed that the disorder be referred to as VLDLR-associated cerebellar hypoplasia. The clinical features of nonprogressive cerebellar ataxia and mental retardation were associated with inferior cerebellar hypoplasia and mild cerebral gyral simplification.

History

In 8 affected children with dysequilibrium syndrome, defined as an autosomal recessive form of cerebral palsy, Gustavson et al. (1977) found low serum dopamine-beta-hydroxylase activity. They interpreted this as indicative of diminished activity of the sympathetic nervous system in this syndrome.

The Hutterites originated from one of several Anabaptist groups formed during the Protestant Reformation in the 16th century and have lived on the North American prairies since the late 1800s (Hostetler, 1985). According to the estimate of Nimgaonkar et al. (2000), the population numbered more than 40,000 individuals, most of whom were descendants of 89 founders. Over 30 different autosomal recessive conditions had been described in the Hutterite population (Innes et al., 1999).