MYH9-related disorders display heterogeneous kidney involvement and outcome

Abstract

BackgroundMYH9-related diseases (MYH9-RD) are autosomal dominant disorders caused by mutations of the MYH9 gene encoding the non-muscle myosin heavy chain IIA. They are characterized by congenital thrombocytopenia, giant platelets and leucocyte inclusions. Hearing impairment, pre-senile cataract and nephropathy can also occur. We aimed to evaluate renal involvement and outcome in MYH9-RD patients followed-up by nephrologists.MethodsWe conducted a retrospective multicentre observational study of 13 patients among 9 families with MYH9 mutation diagnosed by genetic testing and immunofluorescence assay referred to nephrologists.ResultsAt initial referral, median age was 30 (range 14–76) years. Median estimated glomerular filtration rate was 66 mL/min/1.73 m2 (0–141) and two patients had already end-stage renal disease (ESRD). Renal presentation associated proteinuria (n = 12), haematuria (n = 6) and hypertension (n = 6). Three patients developed a rapid onset ESRD whereas five others had a relatively stable kidney function over a 3-year median follow-up (1–34). Extra-renal features varied widely, with hearing impairment in six patients, cataract in two and mild liver dysfunction in seven. Thrombocytopenia existed at referral in 11 patients. Time to diagnosis varied from 0 to 29 years (median 3 years). Initial diagnoses such as idiopathic thrombocytopenic purpura (n = 4) and focal segmental glomerulosclerosis (n = 1) led to corticosteroid administration (n = 4), intravenous immunoglobulins (n = 3), cyclophosphamide (n = 1) and splenectomy (n = 1).ConclusionsRenal involvement and outcome in MYH9-RD are heterogeneous. The diagnosis is often delayed and misdiagnoses can lead to unnecessary treatments. MYH9-RD should be considered in any patient with glomerular involvement associated with a low or slightly decreased platelet count and/or hearing loss and liver dysfunction.

Regulation of the Actin Cytoskeleton in Podocytes

“…Most notable in regards to podocytes are mutations in the MYH9 gene, which encodes non-muscle myosin class II isoform A, and MYO1E , which is a membrane-associated class I myosin [ 185 , 186 ]. Mutations in MYH9 are associated with an autosomal dominant pattern of familial nephritis, deafness, and macrothrombocytopenia but has been reported to have significant variation in the degree of renal disease [ 187 ]. On the other hand, MYO1E is a recessive mutation associated with FSGS without extrarenal manifestations, likely due to the specialized location and the role MYO1E plays in the podocyte [ 185 ].…”

Linking the Landscape of MYH9-Related Diseases to the Molecular Mechanisms that Control Non-Muscle Myosin II-A Function in Cells

“…It is usually very aggressive, and it initially features proteinuria, sometimes with microhematuria, and rapid progression to chronic kidney disease that often requires transplantation [2]. The most severe cases of nephrotic failure have been described as coming from patients with motor domain mutations of MHCII-A [39,40].…”

MYH9-related disease: it does exist, may be more frequent than you think and requires specific therapy

“…As an example, Tabibzadeh et al . report one family with members reaching ESRD at ages ranging from 24 to 78 years [1]. An analysis of the family incidence of more constant features of the disease, such as macrothrombocytopenia, may be more informative.…”

“…Tabibzadeh et al . provide an overview of the spectrum of kidney disease [1]. At Nephrology referral, median age was 30 years (range 14–76) and estimated glomerular filtration rate 66 mL/min/1.73 m 2 , but around 20% were already in ESRD and an additional 50% progressed to ESRD.…”

“…In this issue of ckj , Tabibzadeh et al report one of the largest series of patients with MYH9 mutations and kidney disease [1]. This offers the opportunity to emphasize some key concepts to lower the suspicion threshold and improve outcomes, complementing excellent recent reviews [2–4].…”