A rare case of muscular dystrophy with POMT2 and FKRP gene mutation. Present by : Ghasem Khazaei Supervisor :Dr Mina Mohammadi Sarband

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2 A rare case of muscular dystrophy with POMT2 and FKRP gene mutation Present by : Ghasem Khazaei Supervisor :Dr Mina Mohammadi Sarband

3 Index : Congenital muscular dystrophy (CMD) Dystroglycanopathies Walker-Warburg syndrome (WWS) Limb-girdle muscular dystrophy (LGMD) Case Presentation Conclusion 3

4 CMD A clinically and genetically heterogeneous group of inherited muscle disorders. Affected children may present delay or arrest of gross motor development joint and/or spinal rigidity Muscle weakness joint contractures spinal deformities respiratory compromise 4

5 Defect Subtype Gene Protein Defects of structural protein Laminin alpha-2 deficiency(mdc1a) Collagen VI-deficient CMD LAMA2 COL6A1 COL6A2 COL6A3 POMT1 Laminin α2 Collagen VI Collagen VI Collagen VI Protein-Omannosyltransferase 1 POMT2 Protein-Omannosyltransferase 2 FKTN Fukutin Defects of glycosylation Dystroglycanopathy FKRP LARGE1 Fukutin-related protein Glycosyltransferase-like protein LARGE1 POMGNT1 O-linked mannose β1,2-nacetylglucosaminyltransferase ISPD Isoprenoid synthase domaincontaining 5 protein

6 Defect Subtype Gene Protein Defects of proteins of the endoplasmic reticulum SELENON(SEPN1)- related myopathy SELENON(SEPN1) Selenoprotein N Defects of nuclear envelope proteins LMNA-related CMD (L-CMD) LMNA Lamin A/C 6

7 Dystroglycanopathies Characterized by a broad CMD phenotypic spectrum with and without intellectual disability, eye involvement, and brain findings. Several CMD phenotypes known to be dystroglycanopathies : Walker Warburg syndrome (WWS) Limb-girdle muscular dystrophy (LGMD) 7

8 Walker-Warburg syndrome (WWS) The most severe form of a group of disorders known as congenital muscular dystrophies. An inherited disorder that affects development of the muscles, brain, and eyes. Commonly mutated genes were discovered first, including POMT1, POMT2, ISPD, FKTN, FKRP, and LARGE1. This condition is inherited in an autosomal recessive pattern. 8

9 Limb-girdle muscular dystrophy (LGMD) The age of onset of muscle weakness in late childhood or adulthood that defines LGMD. Individuals with LGMD generally show weakness and wasting restricted to the limb musculature, proximal greater than distal. muscle degeneration/regeneration on muscle biopsy (dystrophic changes). 9

10 LGMD Inflammatory myopathy should be excluded during the diagnostic process. Onset, progression, and distribution of the weakness and wasting vary considerably among individuals and genetic subtypes. The term LGMD1 (including, e.g., LGMD1A, LGMD1B) refers to genetic types showing dominant inheritance, whereas LGMD2 refers to types with autosomal recessive inheritance. 10

11 LGMD Pathogenic variants at more than 50 loci have been reported, making accurate diagnosis and genetic counseling a challenge. an LGMD phenotype and pathogenic variants in POMT1, FKTN, POMGNT1, or POMT2 have been reported. Estimates of prevalence for all forms of LGMD range from one in 14,500 to one in 123,

12 % of Individuals with AR LGMD Up to 68% of individuals with childhood onset and ~10% with adult onset ~10% ~5% Disease Name (Synonym) Alpha-sarcoglycanopathy (LGMD2D) Beta-sarcoglycanopathy (LGMD2E) Gamma-sarcoglycanopathy (formerly SCARMD) (LGMD2C) Delta-sarcoglycanopathy (LGMD2F) Calpainopathy (LGMD2A) Dysferlinopathy (LGMD2B) Gene SGCA SGCB SGCG SGCD CAPN3 DYSF 3% LGMD2G TCAP Unknown LGMD2H TRIM32 6% LGMD2I (MDDGC5) FKRP 12

13 % of Individuals with AR LGMD Disease Name (Synonym) Gene Unknown LGMD2J TTN Unknown LGMD2K (MDDGC1) POMT1 ~25% in the UK population LGMD2L ANO5 Unknown LGMD2M (MDDGC4) FKTN Unknown LGMD2N (MDDGC2) POMT2 Unknown LGMD2O (MDDGC3) POMGNT1 Unknown LGMD2Q PLEC 13

14 Autosomal Recessive LGMD: Clinical Findings Disease Name (Synonym) / Ge ne LGMD2N / POMT2 Presentation Symptoms Weakness Calf Muscle Slowness in running and getting up None Hypertrophy of calves Other Findings Contractures/ Scoliosis Scapular winging and mild lordosis; intellectual disability LGMD2I / FKRP Difficulty run, walk Proximal; upper > lower limb Hypertrophy Rare, late 14

15 Type Serum CK Concentration Muscle Biopsy Histology Muscle Protein (Biochemical) Testing LGMD2N 4-50x normal Muscular dystrophy often with inflammatory infiltrates Decreased glycosylated alphadystroglycan LGMD2I Normal to greatly elevated Muscle fiber size variation with type 1 fiber predominance and necrotic and regenerating fibers Variably decreased glycosyla ted alphadystroglycan; slight reduction of laminin alpha

16 Protein O-mannosyltransferase 2 (POMT2) POMT2 mutations have been identified in congenital muscular dystrophy patients with a wide range of clinical involvement, ranging from the severe muscle-eye-brain disease and Walker-Warburg syndrome to limb girdle muscular dystrophy without structural brain or ocular involvement. 16

17 Case Presentation 17

18 Case Presentation Mr. 33 years old with: Myopathy Slowness in running since age of 13 yrs Prominent calves Gowers' sign Scapular winging 18

19 Case Presentation Test results : Radiology: Scolyosis with some degrees of rotation is seen in iumbar spine. Biopsy: Multiple small groups of necrotic/regenerative fibers with some nuclear clumps and Few myophagocytoses Becker ( - ) DMD gene deletion analysis by multiplex PCR and this patient not be affected with DMD/BMD 19

20 Case Presentation Test results : LGMD ( - ) No mutation was found in coding regions of Calpain 3 (CAPN3) gene (LGMD 2 A - ) CK = 1834 Aldolas =

21 Case Presentation Requested : Panel myopathy NGS Gene Nucleic Acid Alteration Amino Acid Alteration Zygosity Chr _ location POMT2 c.296g>t p.arg99leu Hom Chr 14 FKRP c.427c>a p.arg143ser Het Chr 19 21

22 Case Presentation So requested Sanger sequencing for the known mutation of POMT2 gene for his parents and his brother. The same heterozygous mutation was found in his parents and his brother. 22

23 Conclusion There are 12 cases report of this disease: Italy 6 cases France 4 cases UK 2 cases in view of the remarkable mild clinical picture, we propose to this phenotype as LGMD2N. 23

24 Thank you 24