Cerebellar Ataxia, Impaired Intellectual Development, and Disequilibrium Syndrome-2: Expanding the Phenotype
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction
Pathogenic variants in the WDR81 gene are associated with cerebellar ataxia, impaired intellectual development, and disequilibrium syndrome-2 (CAMRQ2). This disorder is characterized by congenital cerebellar ataxia, intellectual disability, and gait abnormalities. This disorder is extremely rare with fewer than 20 previously published cases in the literature. Previously published cases describe other varying features including thoracic kyphosis and scoliosis, short stature, absent or limited speech, intention tremor, coarse facial features, hirsutism, strabismus, wide and short neck, and small hands and feet. Findings on brain MRI of previously published cases include cerebellar atrophy, generalized brain atrophy, and hypoplasia of the corpus callosum. All previously published cases have occurred in consanguineous families and the majority of affected individuals ambulated with a quadrupedal gait. Here we describe a case report of a more mildly affected female with bipedal gait from a nonconsanguineous family, expanding the phenotype of this rare disorder.
Case Presentation
The patient was twin A of a dizygotic-diamniotic pregnancy. She was transferred to the neonatal intensive care unit (NICU) due to hypoglycemia and vomiting. NICU course included neurology consult for apneic episodes and concern for subclinical seizures. Head ultrasound reported multiple punctate echogenic foci in the basal ganglia bilaterally, but no structural abnormalities were reported on brain MRI at 5 days of age. Electroencephalogram (EEG) was normal in the NICU and she was discharged at 10 days of age. Over time it was noted that she was not attaining milestones at the same pace as her twin. She had difficulty feeding, difficulty sitting unassisted, and walked at 16-18 months of age but with an unsteady gait and frequent falls. She was evaluated by neurology diagnosed with cerebellar ataxia. Brain MRI reported cerebellar atrophy, most pronounced in the vermis, with ex-vacuo dilation of the fourth ventricle. She was evaluated by multiple other subspecialties and had nondiagnostic work-up including spine MRI, cardiac evaluation, ophthalmology evaluation, biochemical testing for inborn errors of metabolism, ataxia gene panel, spinal muscular atrophy gene testing, chromosome microarray, and whole exome sequencing trio with mitochondrial DNA analysis. The family relocated and the patient was re-referred to clinical genetics at 5 years of age. She was noted to have cerebellar ataxia and frequent falls, hypotonia, and mild nystagmus, but no other medical conditions. She receives physical and occupational therapies. She was evaluated for speech therapy but did not qualify for services. She is working at grade level in school with tutoring support but without formal academic interventional services. Family history is negative for similarly affected individuals and consanguinity was denied.
Diagnostic Workup
Re-analysis of the data from previous whole exome trio reported a homozygous pathogenic variant in WDR81, c.2567 C>T [p.(P856L)]. Each parent was found to be heterozygous for this variant, consistent with autosomal recessive inheritance.
Discussion
Previously published cases of CAMRQ2 are characterized by severe intellectual disability including limited or absent speech, with most affected individuals using quadrupedal ambulation secondary to inability to walk with a bipedal gait. Our patient has a notably milder developmental phenotype. She has age-appropriate speech skills and bipedal gait (though with ataxia and frequent falls). Our patient demonstrates previously undescribed phenotypic variability with cerebellar ataxia but otherwise age-appropriate development.
Conclusion
This case highlights the importance of iterative genetic testing and shows how gains in information and technology over time can identify rare diagnoses. In our patient's case, early diagnosis allowed for targeted therapies, such as physical and occupational therapy, which have contributed to a more favorable outcome compared to reported cases of CAMRQ2 presenting with quadrupedal ambulation and severe intellectual disability.
Pathogenic variants in the WDR81 gene are associated with cerebellar ataxia, impaired intellectual development, and disequilibrium syndrome-2 (CAMRQ2). This disorder is characterized by congenital cerebellar ataxia, intellectual disability, and gait abnormalities. This disorder is extremely rare with fewer than 20 previously published cases in the literature. Previously published cases describe other varying features including thoracic kyphosis and scoliosis, short stature, absent or limited speech, intention tremor, coarse facial features, hirsutism, strabismus, wide and short neck, and small hands and feet. Findings on brain MRI of previously published cases include cerebellar atrophy, generalized brain atrophy, and hypoplasia of the corpus callosum. All previously published cases have occurred in consanguineous families and the majority of affected individuals ambulated with a quadrupedal gait. Here we describe a case report of a more mildly affected female with bipedal gait from a nonconsanguineous family, expanding the phenotype of this rare disorder.
Case Presentation
The patient was twin A of a dizygotic-diamniotic pregnancy. She was transferred to the neonatal intensive care unit (NICU) due to hypoglycemia and vomiting. NICU course included neurology consult for apneic episodes and concern for subclinical seizures. Head ultrasound reported multiple punctate echogenic foci in the basal ganglia bilaterally, but no structural abnormalities were reported on brain MRI at 5 days of age. Electroencephalogram (EEG) was normal in the NICU and she was discharged at 10 days of age. Over time it was noted that she was not attaining milestones at the same pace as her twin. She had difficulty feeding, difficulty sitting unassisted, and walked at 16-18 months of age but with an unsteady gait and frequent falls. She was evaluated by neurology diagnosed with cerebellar ataxia. Brain MRI reported cerebellar atrophy, most pronounced in the vermis, with ex-vacuo dilation of the fourth ventricle. She was evaluated by multiple other subspecialties and had nondiagnostic work-up including spine MRI, cardiac evaluation, ophthalmology evaluation, biochemical testing for inborn errors of metabolism, ataxia gene panel, spinal muscular atrophy gene testing, chromosome microarray, and whole exome sequencing trio with mitochondrial DNA analysis. The family relocated and the patient was re-referred to clinical genetics at 5 years of age. She was noted to have cerebellar ataxia and frequent falls, hypotonia, and mild nystagmus, but no other medical conditions. She receives physical and occupational therapies. She was evaluated for speech therapy but did not qualify for services. She is working at grade level in school with tutoring support but without formal academic interventional services. Family history is negative for similarly affected individuals and consanguinity was denied.
Diagnostic Workup
Re-analysis of the data from previous whole exome trio reported a homozygous pathogenic variant in WDR81, c.2567 C>T [p.(P856L)]. Each parent was found to be heterozygous for this variant, consistent with autosomal recessive inheritance.
Discussion
Previously published cases of CAMRQ2 are characterized by severe intellectual disability including limited or absent speech, with most affected individuals using quadrupedal ambulation secondary to inability to walk with a bipedal gait. Our patient has a notably milder developmental phenotype. She has age-appropriate speech skills and bipedal gait (though with ataxia and frequent falls). Our patient demonstrates previously undescribed phenotypic variability with cerebellar ataxia but otherwise age-appropriate development.
Conclusion
This case highlights the importance of iterative genetic testing and shows how gains in information and technology over time can identify rare diagnoses. In our patient's case, early diagnosis allowed for targeted therapies, such as physical and occupational therapy, which have contributed to a more favorable outcome compared to reported cases of CAMRQ2 presenting with quadrupedal ambulation and severe intellectual disability.