Malattia di Pompe. Inquadramento clinico. Dr. S. Zoccolella

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1 Malattia di Pompe Inquadramento clinico Dr. S. Zoccolella

2 Malattia di Pompe Estrema variabilità in termini di: Età d esordio Sede d esordio e quadro clinico Progressione/prognosi

3 Malattia di Pompe Forma infantile classica (esordio entro il primo anno di vita) Altre forme : Infantile non classica Giovanile Late-onset

4 Età esordio Muscolatura Scheletrica Forma Infantile classica < 12 mesi (generalmente nei primi mesi di vita) Ipotonia grave e progressiva (floppy infant) Forma Infantile non classica < 2aa Ipotonia progressiva Capacità Motorie Ritardo nell acquisizione Ritardo nell acquisizione Respirazione Infezioni respiratorie ricorrenti Infezioni respiratorie ricorrenti Cuore Prognosi Cardiomiopatia ipertrofica Aritmie Insufficienza cardiorespiratoria Morte generalmente entro 12 mesi Possibile lieve cardiomiopatia variabile

5 Forma Infantile non classica N= 118

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7 Gross motor weakness, motor speech deficits, sensorineural and/or conductive hearing loss, osteopenia, gastroesophageal reflux, and dysphagia with aspiration risk. Seven of 11 patients were independently ambulatory and four required the use of assistive ambulatory devices.

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9 Forma Giovanile Forma dell Adulto Età esordio Muscolatura Scheletrica Capacità Motorie Respirazione Cuore >2 aa, <18 aa Miopatia prevalentemente prossimale del tronco e degli arti inferiori Possibile regressione delle tappe motorie Possibili problemi respiratori a partire dalla II decade di vita Generalmente nessun interessamento cardiaco > 18 aa Miopatia prevalentemente prossimale del tronco e degli arti inferiori Possibile perdita delle capacità motorie Dispnea da esercizio Apnea durante il sonno Infezioni respiratorie Insuff respiratoria Generalmente nessun interessamento cardiaco

10 Late-onset Pompe

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14 94 patients aged between 25 and 75 years were included in the study. Unfamiliar features: ptosis (23%) bulbar weakness (28%)

15 Lingual weakness present in all cases

16 Adult-onset Pompe disease Sintomi Respiratori In 1\3 dei casi sintomo d esordio della malattia In 1\3 dei casi unico sintomo Ipoventilazione notturna Riduzione 10% della CV in ortostatismo (disfx diaframmatica) Apnee ostruttive Respiratory muscle pressure, polysomnography and nocturnal oximetry

17 Common in the infantile-onset, information on the prevalence in adult onset is scarce 72% of patients had impaired hearing thresholds in at least one ear All patients had a sensorineural type of hearing loss, pointing to cochlear or retrocochlear pathology. Evidence of glycogen storage in the organ of Corti in knock-out mice with Pompe disease 21% of patients had a clinically relevant hearing loss (16% slight, 3% moderate, 2% profound). Prevalence similar to age/sex matched general population

18 Adult-onset Pompe disease Cardiac symptoms Incidence not well documented Typically cardiomyopathy is not observed (Unrecognized?) The lack of significant cardiomyopathy in adult onsed is believed to be relted to residual levels of enzyme activity in cardiac tissue that are higher, compared to infantile onset cases Wolf Parkinson White up to 10% of cases (selective accumulation of glycogen in the conduction system of the heart, even in the absence of hypertrophic cardiomyopathy) In 10% of cases Holeter ECG abnormalities in absence of echocardiographic signis of cardiomyopathy

19 Adult-onset Pompe disease Pain Unrecognized 50% refers pain in at least one muscle district

20 Muller-Felber et al. Neuromusc Disord :

21 Altri sintomi Costipazione Contratture Deformita scheletriche Osteoporosi

22 Late-onset Pompe N= 426

23 Unrecognized, unreported complication, Second cause of death (after respiratory failure) in Pompe disease Cerebral aneurysms and arteropathies have been reported in pts with lateonset Pompe. Several cases of death due to cerebral aneurysms have been reported, one study found a prevalenze of cerebral anuerysms of 2.7%, 4/6 pts had brain vascular abnormalities

24 Multiple microbleeds, MRI features resembling cerebral amyloid No risk factors for IH Autopsy studies revealing glycogen accumules in muscle cells of cerebral arteries

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27 Differential diagnosis of late-onset Pompe disease. Disorder type Diagnoses Dystrophies Limb-girdle muscular dystrophy Dystrophinopathies (Duchenne and Becker muscular dystrophy) Myofibrillar myopathy Myotonic dystrophy type 2 Scapuloperoneal syndromes Danon disease X-linked myopathy with excessive autophagy Inflammatory myopathies Congenital myopathies Other metabolic myopathies Motor neuron disorders Neuromuscular junction disorders Facioscapulohumeral muscular dystrophy Polymyositis Inclusion body myositis Nemaline rod myopathy Central core and multiminicore myopathy Centronuclear myopathy Hyaline body myopathy Other congenital myopathies Debranching enzyme deficiency Branching enzyme deficiency McArdle disease (late-onset) Mitochondrial myopathy Lipid disorder myopathies Spinal muscular atrophy types II and III Kennedy disease Amyotrophic lateral sclerosis Myasthenia gravis Congenital myasthenic syndromes Lambert-Eaton syndrome

28 Adult-onset Pompe disease Delay in the diagnosis: by age Early (n 118) Late onset (426)

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30 Adult-onset Pompe disease Delay in the diagnosis: by symptoms Early (n 118) Late onset (426)

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34 Laboratory testing Ck levels are elevated (ranging from 1.5 to 15 times in adults; usually below 1000) Unlikely rabdomyolysis Serum transaminases may also be increased, with normal ggt

35 Electromyographic pattern Data from a case series The most common feature is a myopathic pattern 30% also presents fibrillations, positive sharp waves, repetitive discharges 10% myotonic discharges 18% normal 1/3 of cases muscle biopsy was unconclusive and needed to be repeated

36 TC Muscolo RM Muscolo

37 Muscle imaging Correlation between muscle weakness and abnormal findings in both CT and MR images Atrophy and fatty infiltration Often Gd + Not specific No aid in establishing a definite diagnosis

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39 DBS (dried blood spots) was used to screen for Pompe disease in the two largest neuromuscular clinics and one of the main respiratory centers in Denmark. 103 Patients with: unclassified LGDM (limb-girdle muscular dystrophy) idiopathic elevation of creatine kinase unexplained myopathy on muscle biopsy unexplained restrictive respiratory insufficiency or unspecified myopathy 3 patients with Pompe disease (8% of the unclassified LGMD group) were identified (with patogenic mutation in the GAA gene) At the time of the study only six cases of Pompe Disease were known in Denmark Conclusions: DBS should be considered early in the diagnostic work-up of patients with an LGMD phenotype, to rule out Pompe disease.

40 None of muscle biopsies contained vacuoles or glycogen accumulation

41 Red flags" more compatible with Pompe disease than LGMD: 1) Mild non-dystrophic, myopathic features on muscle biopsy; 2) Creatine kinase levels below 1000; 3) Disproportionate axial and respiratory muscle involvement in comparison with limb muscle involvement.

42 Prognosis Muscle strength and pulmonary dysfunction deteriorated significantly during follow up

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45 Prognosis Longer disease duration (>15 years) Pulmonary involvement (forced vital capacity in sitting position <80%) at study entry predicted faster decline.

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