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Background
Hereditary
spastic paraplegias (HSP), a group of genetically heterogeneous neurological
disorders with more than 56 documented loci (SPG1-56), are described either
as uncomplicated (or pure), or complicated where in addition to spasticity
and weakness of lower extremeties, additional neurological symptoms are
present, including dementia, loss of vision, epilepsy, mental retardation and
ichthyosis. We identified a large consanguineous family of Indian descent
with four affected members with childhood onset HSP (SPG54), presenting with
upper and lower limb spasticity, mental retardation and agenesis of the
corpus callosum.
Results
A common region
of homozygosity on chromosome 8 spanning seven megabases (Mb) was identified
in the affected individuals using the Illumina human cytoSNP-12 DNA
Analysis BeadChip Kit. Exome sequencing identified a homozygous stop gain
mutation (pR287X) in the phospholipase A1 gene DDHD2, in the
affected individuals, resulting in a premature stop codon and a severely
truncated protein lacking the SAM and DDHD domains crucial for
phosphoinositide binding and phospholipase activity.
Conclusion
This mutation
adds to the knowledge of HSP, suggests a possible founder effect for the pR287X
mutation, and adds to the list of genes involved in lipid metabolism with a
role in HSP and other neurodegenerative disorders.
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Abstract
Perrault syndrome (PRLTS)
is a clinically and genetically heterogeneous disorder. Both male and female
patients suffer from sensory neuronal hearing loss in early childhood, and
female patients are characterized by premature ovarian failure and infertility
after puberty. Clinical diagnosis may not be possible in early life, because
key features of PRLTS, for example infertility and premature ovarian failure,
do not appear before puberty. Limb spasticity, muscle weakness, and
intellectual disability have also been observed in PRLTS patients. Mutations
in five genes, HSD17B4, HARS2, CLPP, LARS2, and C10orf2, have been reported
in five subtypes of PRLTS. We discovered a consanguineous Saudi family with
the PRLTS3 phenotype showing an autosomal recessive mode of inheritance. The
patients had developed profound hearing loss, brain atrophy, and lower limb
spasticity in early childhood. For molecular diagnosis, we complimented
genome-wide homozygosity mapping with whole exome sequencing analyses and
identified a novel homozygous mutation in exon 6 of CLPP at chromosome
19p13.3. To our knowledge, early onset with regression is a unique feature of
these PRLTS patients that has not been reported so far. This study broadens
the clinical spectrum of PRLTS3.
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