WDR81 – Cerebellar Ataxia, Intellectual Disability, and Dysequilibrium Syndrome 2

Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2 (CAMRQ2) is a rare autosomal recessive disorder characterized by congenital cerebellar dysfunction, impaired coordination, gait abnormalities, and cognitive delay. Pathogenic variants in WDR81 underlie Cerebellar Ataxia, Impaired Intellectual Development, and Dysequilibrium Syndrome 2, with initial linkage identified in a consanguineous family carrying a private missense mutation p.Pro856Leu in four affected individuals (PMID:22686558).

An independent case of a mildly affected female from a non-consanguineous family exhibited developmental delay, hypotonia, feeding difficulties, and an unsteady gait; reanalysis at age five uncovered a homozygous pathogenic WDR81 variant in a single proband (PMID:40013199). Together, these reports account for 5 probands across two unrelated families, confirming autosomal recessive inheritance and clear segregation of WDR81 variants.

Affected individuals present with hypotonia (HP:0001252), ataxia (HP:0001251), unsteady gait (HP:0002317), and feeding difficulties (HP:0011968), often accompanied by cerebellar atrophy, scoliosis, thoracic kyphosis, short stature, intention tremor, and downbeat nystagmus, thereby broadening the phenotypic spectrum of CAMRQ2.

WDR81 encodes a WD‐repeat protein highly expressed in Purkinje and photoreceptor cells. In the ENU‐induced nur5 mouse model, a missense L1349P mutation produces tremor, abnormal gait, Purkinje cell degeneration, and photoreceptor loss; these phenotypes are fully rescued by a wild-type Wdr81 transgene, supporting loss of function as the pathogenic mechanism (PMID:23595742).

No studies have refuted this association. Clinical and experimental data converge to establish a robust gene–disease link.

Key Take-home: WDR81 should be a primary candidate in genetic testing of early-onset cerebellar ataxia with intellectual disability, even in non-consanguineous cases, to expedite diagnosis and guide management.

References

• Ophthalmic genetics • 2012 • Neuro-ophthalmologic findings in humans with quadrupedal locomotion. PMID:22686558
• Cureus • 2025 • Cerebellar Ataxia, Impaired Intellectual Development, and Disequilibrium Syndrome-2: A Case Report. PMID:40013199
• The Journal of neuroscience : the official journal of the Society for Neuroscience • 2013 • WDR81 is necessary for purkinje and photoreceptor cell survival. PMID:23595742

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