Atypical Chédiak-Higashi syndrome with attenuated phenotype: three adult siblings homozygous for a novel LYST deletion and with neurodegenerative disease

Abstract

BackgroundMutations in LYST, a gene encoding a putative lysosomal trafficking protein, cause Chédiak-Higashi syndrome (CHS), an autosomal recessive disorder typically characterized by infantile-onset hemophagocytic syndrome and immunodeficiency, and oculocutaneous albinism. A small number of reports of rare, attenuated forms of CHS exist, with affected individuals exhibiting progressive neurodegenerative disease beginning in early adulthood with cognitive decline, parkinsonism, features of spinocerebellar degeneration, and peripheral neuropathy, as well as subtle pigmentary abnormalities and subclinical or absent immune dysfunction.MethodsIn a consanguineous Pakistani kindred with clinical phenotypes consistent with attenuated CHS, we performed SNP array-based homozygosity mapping and whole gene sequencing of LYST.ResultsWe identified three individuals homozygous for a novel six base pair in-frame deletion in LYST (c.9827_9832ATACAA), predicting the loss of asparagine and threonine residues from the LYST transcript (p.Asn3276_Thr3277del), and segregating with the phenotype in this family.ConclusionsWe further characterize the neurologic features of the attenuated form of CHS, and discuss pathophysiologic mechanisms underlying the neurodegenerative components of CHS. Attenuated CHS is phenotypically heterogenous and should be considered when young adults develop neurodegenerative disease and have pigmentary abnormalities. We briefly discuss surveillance and management of patients with CHS-related neurodegeneration.

Chediak-Higashi syndrome: Lysosomal trafficking regulator domains regulate exocytosis of lytic granules but not cytokine secretion by natural killer cells

“…Mutations in LYST were identified in all subjects, and were previously reported for some of the cases (Table E1). 6, 24, 25 Voluntary healthy donors were recruited at the NIH, with informed consent, in accordance with the Declaration of Helsinki.…”

Optic neuropathy in late-onset neurodegenerative Chédiak–Higashi syndrome

“…Three adult siblings presented with a late-onset neurodegenerative phenotype of genetically confirmed CHS, and were reported previously 7. Their parents were of Pakistani ethnicity, with the paternal great-grandmother sharing the maternal lineage.…”

“…In 10–15% of cases, a late-onset neurodegenerative phenotype with minimal to no immunological dysfunction occurs. These cases have been historically associated with missense mutations or small intragenic deletions that do not disrupt the reading frame 6 7. Classic neurological disease in attenuated forms, and also observed in classic infantile disease decades after haematopoietic stem cell transplantation,8 includes peripheral neuropathy, cerebellar ataxia and progressive cognitive decline.…”

Inflammatory demyelinating neuropathy heralding accelerated chediak‐higashi syndrome

“…Progressive neurological disturbances are a hallmark of surviving patients. Although it is effective for treating the hematological and immunological complications, bone‐marrow transplantation seems to have no effect on neurological manifestations, which tend to follow a progressive course …”