Saturday, February 21, 2009

Glycogenosis type II in adults

Bembi et al. Diagnosis of glycogenosis type II. Neurology 2008; 71: S2: S4-S11.
Also known as glycogen storage disease type II, Pompe d or acid maltase deficiency caused by a mutation in the gene encoding acid alpha-glucosidase (GAA) enzyme leading to accumulation of glycogen in lysosomes of several tissues including cardiac skeletal and smooth muscle cells.

In juvenile/adult type, phenotype may vary somewhat and more than 200 mutations of the GAA gene are reported. In adults, skeletal muscle involves the proximal lower limbs, and paraspinal muscles often followed by severe diaphragmatic and accessory muscle failure. Complaints may include exertional pain, cramps and aches, back pain, slow disease progression. Respiratory involvement may occur early and may be presenting symptom in 30 % of cases. Sleep apnea, exertional dyspnea and RTI's are common.

Evaluation should include CPK (high in 95%), ALT, AST, DH, +/- urinary Glc4 . NCS are normal. EMG is nonspecific shows fibs, myotonic and myopathic findings. Classic muscle biopsy may show acid phos positive cytoplasmic vacuoles but may be negative. Biochemical assays for GAA activity are often needed to confirm. Skeletal muscle or skin fibroblasts may be used. Molecular analysis of the gene may also be needed. In adults cardiac muscles is usually not affected, unlike infants and juveniles.

The differential diagnosis includes Becker, limb girdle, scapuloperoneal, rigid spine s, other glycogen related diseases (debrancher deficiency, branching enzyme def, myophosphorylase def, PFK def, Danon disease, mitochondrial disease, polymyositis.

MRI's in adults (n=11) with confirmed disease showed adductor magnus, semimembranosus, semitendinosis involved early on. Later, fatty infltration occurs in long head of biceps femoris, 3 heads of vastus, with SPARING OF SHORT HEAD OF BICEPS, SARTORIUS, RECTUS, GRACILIS AND PERIPHERAL PART OF VASTUS LATERALIS. CALF MUSCLES ARE NORMAL.


Respiratory management: Cough peak expiratory flow (CPEF) is single best test to determine if patient can clear secretions with a threshold value of 160 L/min being adequate. A high negative maximal inspiratory pressure (>80 cm H2O) or high positive maxinal expiratory pressure (>90 cm H2O) excludes relavant inspiratory or expiratory weakness. Sniff expiratory pressure should also be checked.

Sleep disordered breathing refers to central, obstructive or mixed apnea, hypoventilation or both during sleep. SDB occurs in two thirds. Hypoventilation during REM sleep is due to decreased tidal volume especially during REM sleep. OSA may be life threatening. Orthopnea and dyspnea may be late findings. Late tachypnea at rest occurs. On exam look for failure of outward distension of abdomen during breathing (inspiration) accessory recruitment and mucus encumbrance of upper and lower airways.

No outpatient surgery should be done, and anesthesia consulted.

Genetics usually is AR. Risk of being a carrier for a sib of an affected patient is 2/3, and risk of being a carrier for sibs of a parent of an affected patient is 1/2. Risk of an affected child for a sib of an affected patient is > 1/600 and for sibs of a parent, > 1/800.

A clinical trial with a Genzyme drug, alglucosidase alfa resulted in improved walking distance and stabilized pulmonary function over an 18 month period (van der Ploeg et al., A randomized study of alglucosidase alfa in late onset Pompe's disease NEJM 2010; 362: 1396-1406) (, NCT00158600).  Outcome measures were six minute walk and percentage of predicted FVC. 

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