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Co-occurrence of CLCN2-related leukoencephalopathy and SPG56

Almasoudi, Wejdan LU ; Nilsson, Christer LU ; Kjellström, Ulrika LU ; Sandeman, Kevin LU and Puschmann, Andreas LU orcid (2023) In Clinical Parkinsonism and Related Disorders 8.
Abstract

Family Report: Two rare autosomal recessive neurological disorders, leukoencephalopathy with ataxia and spastic paraplegia 56 (SPG56), were found in members of the same family. Two siblings presented with spastic paraplegia, cognitive impairment, bladder and bowel dysfunction and gait ataxia; their consanguineous parents were unaffected. Ophthalmological examination revealed chorioretinopathy. Brain MRI showed T2 hyperintensities and T1 hypointensities in the internal capsules, cerebral peduncles, pyramidal tracts and middle cerebellar peduncles. Both affected siblings were homozygous for CYP2U1 c.947A > T p.(Asp316Val), a known cause for SPG56. However, they were also homozygous for the novel variant CLCN2 c.607G > T,... (More)

Family Report: Two rare autosomal recessive neurological disorders, leukoencephalopathy with ataxia and spastic paraplegia 56 (SPG56), were found in members of the same family. Two siblings presented with spastic paraplegia, cognitive impairment, bladder and bowel dysfunction and gait ataxia; their consanguineous parents were unaffected. Ophthalmological examination revealed chorioretinopathy. Brain MRI showed T2 hyperintensities and T1 hypointensities in the internal capsules, cerebral peduncles, pyramidal tracts and middle cerebellar peduncles. Both affected siblings were homozygous for CYP2U1 c.947A > T p.(Asp316Val), a known cause for SPG56. However, they were also homozygous for the novel variant CLCN2 c.607G > T, p.(Gly203Cys), classified as a variant of unknown significance. Testing of additional family members revealed homozygosity for both variants in an additional brother, whom we initially considered unaffected. Both male CLCN2 carriers were infertile, and review of the literature revealed one reported case with azoospermia, however the brother had no overt signs of SPG56. His testicular biopsy revealed incomplete maturation arrest in spermatogenesis; clinically we found mild memory impairment and hand tremor and MRI showed similar changes as his siblings. We consider CLCN2 c.607G > T pathogenic because of the neuroradiological and clinical findings, including azoospermia. Conclusion: Considerable workup may be required to determine the pathogenicity of novel variants, and to unambiguously associate phenotype with genotype. In very rare disorders, highly specific clinical or biomarker combinations provide sufficient evidence for a variant's pathogenicity. Phenotypic variation of monogenic disorders described in the literature may be attributed to a second co-occurring monogenic disorder, especially in consanguineous families. SPG56 may have reduced penetrance.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
CLCN2, CYP2U1, Electroretinography, Hereditary spastic paraplegia, Leukoencephalopathy, Male infertility, SPG56
in
Clinical Parkinsonism and Related Disorders
volume
8
article number
100189
publisher
Elsevier
external identifiers
  • pmid:36879630
  • scopus:85148675342
ISSN
2590-1125
DOI
10.1016/j.prdoa.2023.100189
language
English
LU publication?
yes
id
45a72a64-04e8-40d2-9735-50191408a102
date added to LUP
2023-03-17 12:55:36
date last changed
2024-05-16 11:42:13
@article{45a72a64-04e8-40d2-9735-50191408a102,
  abstract     = {{<p>Family Report: Two rare autosomal recessive neurological disorders, leukoencephalopathy with ataxia and spastic paraplegia 56 (SPG56), were found in members of the same family. Two siblings presented with spastic paraplegia, cognitive impairment, bladder and bowel dysfunction and gait ataxia; their consanguineous parents were unaffected. Ophthalmological examination revealed chorioretinopathy. Brain MRI showed T2 hyperintensities and T1 hypointensities in the internal capsules, cerebral peduncles, pyramidal tracts and middle cerebellar peduncles. Both affected siblings were homozygous for CYP2U1 c.947A &gt; T p.(Asp316Val), a known cause for SPG56. However, they were also homozygous for the novel variant CLCN2 c.607G &gt; T, p.(Gly203Cys), classified as a variant of unknown significance. Testing of additional family members revealed homozygosity for both variants in an additional brother, whom we initially considered unaffected. Both male CLCN2 carriers were infertile, and review of the literature revealed one reported case with azoospermia, however the brother had no overt signs of SPG56. His testicular biopsy revealed incomplete maturation arrest in spermatogenesis; clinically we found mild memory impairment and hand tremor and MRI showed similar changes as his siblings. We consider CLCN2 c.607G &gt; T pathogenic because of the neuroradiological and clinical findings, including azoospermia. Conclusion: Considerable workup may be required to determine the pathogenicity of novel variants, and to unambiguously associate phenotype with genotype. In very rare disorders, highly specific clinical or biomarker combinations provide sufficient evidence for a variant's pathogenicity. Phenotypic variation of monogenic disorders described in the literature may be attributed to a second co-occurring monogenic disorder, especially in consanguineous families. SPG56 may have reduced penetrance.</p>}},
  author       = {{Almasoudi, Wejdan and Nilsson, Christer and Kjellström, Ulrika and Sandeman, Kevin and Puschmann, Andreas}},
  issn         = {{2590-1125}},
  keywords     = {{CLCN2; CYP2U1; Electroretinography; Hereditary spastic paraplegia; Leukoencephalopathy; Male infertility; SPG56}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Clinical Parkinsonism and Related Disorders}},
  title        = {{Co-occurrence of CLCN2-related leukoencephalopathy and SPG56}},
  url          = {{http://dx.doi.org/10.1016/j.prdoa.2023.100189}},
  doi          = {{10.1016/j.prdoa.2023.100189}},
  volume       = {{8}},
  year         = {{2023}},
}