Woodhouse–Sakati syndrome (WSS) is a rare autosomal recessive disease with characteristic neuro-endocrine manifestations. WSS encompasses heterogeneous phenotypes and disease course.
We aimed to ...characterize neurological involvement of the disease through subgrouping of core neurological manifestations.
A single-institution retrospective analysis of patients with clinically and genetically confirmed diagnosis of WSS.
A total of 38 individuals belonging to 17 families were identified to have WSS. The mean age at enrollment was 30.1 years (range 16–53 years). Neurological involvement was noted in 31 patients (81.5%). Dystonia was the most common neurological manifestation (67%), followed by intellectual disability (45%) and sensorineural hearing loss (30%). Based on the Neurological Impairment Scale (NIS), the disease was recognized to have two distinct patterns. A disabling, rapidly progressive pattern (NIS of 3–4; Type 1) was noted in eighteen patients (12 males, 6 females; 47.4%) with severe disability that occurs within a mean duration of 7.4 ± 3.6 years. Type 2 WSS was identified in twenty patients (8 males, 12 females; 52.6%), and showed either absent or mild neurological involvement with preserved activities of daily living (NIS of 0–1). The mean age of onset for neurological manifestations was earlier in type 1 (12.6 ± 4.5 years) compared to type 2 (18.1 ± 4.3 years). Type 1 WSS has a significantly higher rate of intellectual disability (p= <0.001).
In this pleiotropic syndrome, we identified two distinct phenotypes with variable prognosis. A high Interfamilial and intrafamilial phenotypic variability despite having a similar gene mutation suggests a possible role of genetic or environmental modifying factor.
•Woodhouse-Sakati syndrome (WSS) is a pleiotropic syndrome with variable neurological manifestations.•Two distinct phenotypes were recognized in our study.•Gene modifier factor has potential role to cause interfamilial and intrafamilial phenotypic variability.
Phosphodiesterase 10A (PDE10A) controls body movements by regulating cyclic adenosine monophosphate signaling in the basal ganglia. Two classes of PDE10A variants are reported with distinctive ...genotype-phenotype correlation. The autosomal recessive mutations in the GAF-A and catalytic domains are associated with compromised membrane localization, and manifest with infantile onset chorea, developmental, and cognition delay with normal brain MRI. Conversely, autosomal dominant mutations in the GAF-B domain cause protein aggregates which results in childhood onset chorea in the context of normal cognition and development, with striatal lesions.
Phenotypic characteristics of affected individuals with PDE10A mutations belonging to a single family were recorded. In addition, Sanger sequencing and in silico analysis were used to identify the mutations. Homozygosity mapping was applied together with whole exome sequencing.
Four individuals from a consanguineous family affected with PDE10A mutations were observed for up to 40 years. Although these individuals displayed a clinical phenotype attributed to the recessive GAF-A mutations, they revealed a bi-allelic GAF-B mutation (c.883G > A:p. D295 N; p.Asp295Asn) that was segregated with all affected individuals. In addition to chorea, we observed peculiar foot deformities and pronounced social phobia, with normal brain MRI. In silico structural analysis suggested that the GAF-B mutation blocked allosteric PDE10A activation. The resulting lack of PDE10A activity likely phenocopies GAF-A mutations, and this is achieved through a distinct mechanism.
Collectively, our findings demonstrate the association of recessive and dominant phenotypes of known variants, and further expands the genotype-phenotype landscape of PDE10A-associated movement disorders.
•PDE10A mutations are increasingly recognized in infantile- and childhood-onset chorea.•We report a novel biallelic mutation in the GAF-B domain with phenotype previously described in GAF-A domain mutation.•This work further expands the genotype-phenotype landscape of PDE10A-associated movement disorders.
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