Malattia di Pompe Inquadramento clinico

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Malattia di Pompe Inquadramento clinico
Malattia di Pompe
Inquadramento clinico
Dr. S. Zoccolella
Malattia di Pompe
Estrema variabilità in termini di:
– Età d’esordio
– Sede d’esordio e quadro clinico
– Progressione/prognosi
Malattia di Pompe
• Forma infantile “classica” (esordio entro il
primo anno di vita)
• Altre forme :
– Infantile “non classica”
– Giovanile
– Late-onset
Forma Infantile
classica
Forma Infantile non
classica
Età esordio
< 12 mesi
(generalmente nei primi
mesi di vita)
< 2aa
Muscolatura Scheletrica
Ipotonia grave e
progressiva (floppy
infant)
Ipotonia progressiva
Capacità Motorie
Ritardo nell’acquisizione Ritardo nell’acquisizione
Respirazione
Infezioni respiratorie
ricorrenti
Infezioni respiratorie
ricorrenti
Cuore
Cardiomiopatia
ipertrofica
Aritmie
Insufficienza
cardiorespiratoria
Morte generalmente
entro 12 mesi
Possibile lieve
cardiomiopatia
Prognosi
variabile
Forma Infantile non classica
N= 118
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.
Forma Giovanile
Forma dell’Adulto
Età esordio
>2 aa,
<18 aa
> 18 aa
Muscolatura Scheletrica
Miopatia
prevalentemente
prossimale del
tronco e degli arti
inferiori
Possibile
regressione delle
tappe motorie
Possibili problemi
respiratori a partire
dalla II decade di
vita
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
Capacità Motorie
Respirazione
Cuore
Generalmente
nessun
interessamento
cardiaco
Late-onset Pompe
94 patients aged between 25 and 75 years were included in the study.
Unfamiliar features:
ptosis (23%)
bulbar weakness (28%)
Lingual weakness
present in all cases
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
•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
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
Adult-onset Pompe disease
Pain
• Unrecognized
• 50% refers pain in at least one muscle district
Muller-Felber et al. Neuromusc Disord 2007 17: 698-706
Altri sintomi
•
•
•
•
Costipazione
Contratture
Deformita’ scheletriche
Osteoporosi
Late-onset Pompe
N= 426
•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
• Multiple microbleeds , MRI features resembling
cerebral amyloid
• No risk factors for IH
• Autopsy studies revealing glycogen accumules in
muscle cells of cerebral arteries
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
•Facioscapulohumeral muscular dystrophy
Inflammatory
myopathies
Congenital myopathies
Other metabolic
myopathies
Motor neuron disorders
Neuromuscular junction disorders
•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
Adult-onset Pompe disease
Delay in the diagnosis: by age
Early (n 118)
Late onset (426)
Adult-onset Pompe disease
Delay in the diagnosis: by symptoms
Early (n 118)
Late onset (426)
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
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
TC Muscolo
RM Muscolo
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
•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.
None of muscle biopsies contained vacuoles or glycogen accumulation
“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.
Prognosis
•Muscle strength and pulmonary dysfunction
deteriorated significantly during follow up
Prognosis
•Longer disease duration (>15 years)
•Pulmonary involvement (forced vital capacity
in sitting position <80%) at study entry
predicted faster decline.