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Genetic analysis in three Egyptian patients with Griscelli syndrome Type 1 reveals new nonsense mutations in MYO5A

2020; Oxford University Press; Volume: 45; Issue: 6 Linguagem: Inglês

10.1111/ced.14220

1365-2230

Marwa Abd Elmaksoud, N. S. Gomaa, Hanan Galal Azouz, Charles On, C. T. Ho, Tarek Omar, John A. McGrath, Alexandros Onoufriadis,

Trypanosoma species research and implications

Click here for the corresponding questions to this CME article. Griscelli syndrome Type 1 (GS1; MIN 214450) is a rare autosomal recessive disease caused by mutations in the MYO5A gene.1 The syndrome was first reported in 1978,2 and since then, three subtypes have been identified according to the phenotype and gene involved. In addition to the shared common feature of silvery-grey hair and skin hypopigmentation, there are also primary neurological manifestations in GS1, immune impairment and haemophagocytic lymphohistiocytosis in GS2 (resulting from mutations in RAB27A), or hypopigmentation only in GS3 (mutations in MLPH). Elejalde syndrome (ES), also called neuroectodermal melanolysosomal disease, is characterized by silvery hair, skin hypopigmentation, ophthalmological abnormalities and severe primary neurological dysfunction with no immunological deficit. Mutations in MYO5A also cause ES, but it is still debatable whether or not GS1 and ES are distinct entities.3, 4 To date, about 20 patients with GS1, including those with ES, have been reported.5 Most of these reports have not been confirmed by genetic analysis, making accurate estimation of GS1/ES prevalence very difficult (Table S1).3 The MYO5A gene encodes the myosin Va protein, which interacts with actin to maintain molecular transport within cells. Melanosomal transport requires the integrated action of the MYO5A, RAB27A and MLPH gene products, which explains the common phenotype of pigmentary dilution among the GS subtypes.4 In addition, myosin Va is also essential for the exocytosis of certain substances such as neuropeptides from brain neurons that support synaptic activity, which can explain the neurological manifestations in GS1.6 We report three Egyptian patients – two siblings and an unrelated individual – diagnosed with GS1 (Fig. 1). All patients were born to consanguineous parents and had silvery-grey hair. They all sought medical advice in infancy with varying neurological and cutaneous manifestations (see Table 1 for full details). Following ethics approval (REC reference: 07/H0802/104) and informed consent, DNA was extracted from peripheral blood samples obtained from the probands and their parents. Sanger sequencing of all exons and splice sites of MYO5A revealed two previously unreported mutations. The two siblings (AII:2 and AII:3) were homozygous for a nonsense mutation in exon 18 (c.2110C>T; p.Gln704*), whereas Patient BII:5 was homozygous for a nonsense mutation in exon 5 (c.463C>T; p.Arg155*). Genotyping of the parents' DNA confirmed segregation of the variants, consistent with an autosomal recessive inheritance pattern (Fig. S1). GS1 is characterized by primary neurological deficits, which usually start in early infancy and include hypotonia, developmental delay, intellectual disabilities and seizures, as well as the dermatological features of silvery-grey hair and skin hypopigmentation. One challenge in clinically evaluating patients with GS who have neurological features is to exclude a diagnosis of GS2. Although individuals with GS2 characteristically develop immunological abnormalities and a poor prognosis as a result of RAB27A mutations, they may also have neurological features due to lymphocytic infiltration of the brain or haemophagocytic lymphohistiocytosis. The observation that both GS1 and GS2 can share overlapping neurological abnormalities can make a clinical distinction between the two extremely challenging, and accurate subtyping may require DNA sequencing of MYO5A and RAB27A. Immunotherapy and bone marrow transplantation can improve the neurological (and immunological) features of GS2, but for GS1, only supportive treatment is available, with pharmacological therapies offered to control seizures and intensive physical and mental rehabilitation initiated to boost motor and cognitive development. However, the potential benefits of this intensive supportive intervention were evident in Patient AII:3, for whom diagnosis and interventions started earlier than her comparatively more severely affected brother. In conclusion, clinical recognition of neurological manifestations in GS, supported by genetic testing, is important in establishing an accurate diagnosis that is relevant to treatment and prognosis. Genetic analysis of our GS1 cases expands the mutational spectrum of the disease, and provides early diagnosis and accurate genetic counselling for the families. We thank all the patients and their parents who kindly contributed their samples, and our colleagues at Alexandria University, Dr M. El-Deep and Dr Y. El-Chazli, for their kind assistance. This work was funded and supported by the UK National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre (BRC) award to Guy's and St Thomas' NHS Foundation Trust, in partnership with the King's College London and King's College Hospital NHS Foundation Trust. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. To demonstrate knowledge of the underlying molecular genetic defect and clinical manifestations of Griscelli syndrome Type 1. 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