筋型糖原病

Glycogen storage disease type VII (GSD-VII), or Tarui disease, is a rare autosomal recessive disorder caused by biallelic loss-of-function variants in the PFKM gene encoding the muscle isoform of phosphofructokinase (PFK), a key enzyme of the glycolytic pathway. PFK deficiency impairs glycogen and glucose metabolism in skeletal muscle and erythrocytes, causing exercise intolerance, exertional myalgia, and myoglobinuria, and, in some cases, fixed proximal muscle weakness, as well as haemolytic anaemia. We report the case of an Italian woman with genetically confirmed GSD-VII harbouring a homozygous missense variant in PFKM (NM_000289.6:c.550C>T, p.Arg184Trp). This variant was previously identified in Wachtelhund dogs, a spontaneous animal model of PFK deficiency, but never reported in patients so far. PFK activity in skeletal muscle (PFKM) was found severely decreased and ultrastructural analysis revealed glycogen accumulation and mitochondrial alteration, supporting the pathogenetic role of the identified variant.

BACKGROUND: Pompe disease is an autosomal recessive disorder caused by a deficiency of acid α-glucosidase (GAA) enzyme. This deficiency induces progressive glycogen accumulation, leading to weakness of the respiratory muscle, including the diaphragm. As established enzyme replacement therapy is available for Pompe disease, earlier detection of potential Late-Onset Pompe Disease (LOPD) and subsequent intervention would have a significant clinical impact. PURPOSE: Our hypothesis was that sleep problems, including sleep-disordered breathing (SDB) and clinical symptoms, may indicate an early stage of LOPD, since decreased respiratory muscle activity often presents initially during sleep. The primary aim of the PSSAP-J study was to demonstrate a higher prevalence of LOPD in a sleep-laboratory-based population. Secondary aims included identifying predictive factors for LOPD from diagnostic polysomnography (PSG) findings and clinical symptoms. METHODS: This prospective multicenter observational cohort study enrolled consecutive patients presenting to sleep laboratories for overnight PSG due to suspected SDB. All patients underwent a Dried Blood Spot (DBS) screening for GAA activity. Genetic analysis of the GAA gene was performed for confirmatory testing when indicated. RESULT: A total of 724 participants were analyzed, although the COVID-19 pandemic prevented reaching the target sample size (n = 1,500). No definitive LOPD cases were confirmed among those who completed the confirmatory testing (prevalence 0%; 95% confidence interval [CI], 0.00%-0.51%). However, seven screen-positive patients declined confirmatory testing and were classified as indeterminate cases. Consequently, we could not definitively establish a higher prevalence or identify predictive factors for LOPD in this population. CONCLUSION: Although the primary study aims could not be confirmed due to the sample size shortfall and the presence of indeterminate cases, our findings highlight the importance for sleep physicians to maintain a high index of suspicion for underlying myopathies, such as LOPD, in clinical practice. CLINICAL TRIAL REGISTRATION: UMIN000039191, UMIN Clinical Trials Registry ( http://www.umin.ac.jp/ctr ).

Background and Clinical Significance: Tarui disease, or glycogen storage disease type VII, is a rare autosomal recessive metabolic myopathy caused by muscle phosphofructokinase deficiency. Its manifestations include exercise intolerance, exertional myalgia, muscle cramps, myoglobinuria, rhabdomyolysis, hyperuricemia, and compensated hemolysis. The hematologic phenotype may obscure the underlying metabolic disorder and raise concern for a clonal myeloid neoplasm. Case Presentation: A 23-year-old man was referred for persistent mild thrombocytopenia following evaluation for jaundice and hepatosplenomegaly. He had undergone cholecystectomy at 18 years of age and reported exercise-induced myalgia, muscle cramps, and episodes of dark urine. Laboratory investigations demonstrated mild monocytosis, reticulocytosis, thrombocytopenia, hyperuricemia, elevated lactate dehydrogenase, and predominantly unconjugated hyperbilirubinemia, with a negative direct antiglobulin test. Selected inherited hemolytic disorders, hemoglobinopathies, and paroxysmal nocturnal hemoglobinuria were excluded. Bone marrow examination showed marked erythroid hyperplasia and mild megakaryocytic dysplasia. Testing for JAK2, CALR, and MPL mutations and an extended myeloid next-generation sequencing panel identified no pathogenic variants, and monocytosis resolved during follow-up. Whole-exome sequencing identified a homozygous PFKM missense variant, NM_001354735.1:c.1087A>T, p.(Ile363Phe), classified as a variant of uncertain significance. The patient subsequently developed severe rhabdomyolysis, with a creatine kinase level of 225,000 U/L and recovered after intensive intravenous hydration without renal impairment. Conclusions: Tarui disease should be considered in young patients with compensated hemolysis, hyperuricemia, exertional muscle symptoms, dark urine, or rhabdomyolysis, even when hematologic abnormalities suggest a myeloid disorder. The highly concordant phenotype and homozygous PFKM variant support a clinically probable diagnosis, although pathogenicity remains unconfirmed. Functional and segregation evidence may strengthen causal interpretation and support future variant reclassification.

Paraproteinemic myopathies are rare but potentially treatable disorders caused by pathogenic monoclonal proteins, yet diagnosis is often delayed because of nonspecific clinical manifestations and the lack of standardized diagnostic approaches. The 294th ENMC International Workshop convened 21 experts from 12 countries and two patient representatives to establish international consensus on their diagnosis and management. The workshop reviewed current evidence on sporadic late-onset nemaline myopathy (SLONM), light-chain (AL) amyloid myopathy, vacuolar myopathy with monoclonal gammopathy and stiffness (VAMMGAS), and scleromyxedema-associated myopathy. Clinical red flags include age at symptom onset ≥40 years, subacute proximal and/or axial weakness, normal or mildly elevated creatine kinase levels (except in VAMMGAS), dysphagia, weight loss, systemic manifestations, and poor response to conventional immunotherapy. Consensus diagnostic criteria for SLONM and a diagnostic algorithm for paraproteinemic myopathies were established. Routine Congo red staining of muscle biopsies, particularly in patients with monoclonal protein, was recommended. The workshop endorsed replacing SLONM-MGUS with SLONM-MP to reflect the pathogenic role of the monoclonal protein and recommended plasma cell-directed therapy as the cornerstone of treatment for SLONM-MP and AL amyloid myopathy. These recommendations provide the first international consensus framework for the diagnosis and management of paraproteinemic myopathies and establish priorities for future collaborative research.

PURPOSE: Biallelic pathogenic variants in PYGM (glycogen myophosphorylase) cause glycogen storage disease V (GSDV), a skeletal muscle disorder with reported association with hereditary macular dystrophy (HMD). This study investigated the role of PYGM in HMD and broader retinal disease through clinical and functional analyses. METHODS: An autosomal recessive HMD family underwent phenotyping and genome sequencing. Separately, data from 65 patients with GSDV (mean age = 51.7 years) were analyzed for retinal involvement. Immunohistochemistry, RT-qPCR and translating ribosome affinity purification assays assessed retinal expression of glycogen phosphorylase (GP) isoenzymes. Glycogenolysis was studied in retinal pigment epithelial (RPE-1) cells. Retinal sections from PygmR50*/R50* mice were also examined. RESULTS: Genome sequencing identified a homozygous pathogenic stop-gain variant in PYGM (NM_005609.4:c.148C > T; p.[Arg50*]) in the proband and affected sibling, and re-phenotyping revealed features of GSDV. Retinal involvement was identified in 30 of 65 GSDV cases (23 bilateral), with higher prevalence in participants >60 years (approximately 2.6-fold) and men (approximately 2-fold). PYGM expression was localized to Müller glia and photoreceptors. Cell-type-specific GP isoenzyme expression was found in mouse retina and RPE-1 cells. RPE-1 cells demonstrated glycogenolysis. PygmR50*/R50* mice lacked glycogen accumulation but exhibited photoreceptor outer segment thinning consistent with Pygm being the predominant isoform expressed in mouse photoreceptors. CONCLUSIONS: GSDV is moderately associated with retinopathy, and may present as non-syndromic HMD, warranting retinal monitoring for patients, and the inclusion of PYGM in retinal dystrophy gene panels. Redundancy in retinal glycogenolysis may account for lower penetrance and higher age-related prevalence in patients. Photoreceptor thinning observed in PygmR50*/R50* mice strengthens the association between HMD and GSDV in humans.