Acid maltase deficiency

A patient with adult acid maltase deficiency (AMD) developed severe obstructive sleep apnea (OSA) and respiratory insufficiency. Weaning failure was followed by diffuse pneumonia and death. At autopsy, profound muscle replacement by fibrofatty tissue was noted in the tongue and diaphragm, while the accessory and nonrespiratory muscles were variably preserved. To our knowledge, this case represents the first detailed clinical description of OSA associated with adult AMD. In addition, we suggest that severe tongue weakness due to fatty metamorphosis, in concert with macroglossia, provides a unique pathophysiologic mechanism for OSA.

Acid maltase deficiency (AMD) is a rare genetic disorder in which the lysosomal enzyme m-glucosidase (acid maltase) is markedly deficient. The resultant failure of glycogen degradation leads to progressive glycogen accumulation in tissue. The adult form usually presents as a limb-girdle myopathy with respiratory muscle involvement. Light microscopy typically shows a variable vacuolar myopathy with glycogen-containing vacuoles and progressive replacement of myofibrils by fibrofatty tissue. Lingual involvement has rarely been a prominent feature in adult patients.[1] We report the case of an adult with long-standing AMD and macroglossia who developed severe obstructive sleep apnea (OSA).

CASE REPORT

The patient presented in 1982 at age 55 years with proximal muscle weakness, severe orthopnea, and dyspnea. A detailed workup revealed the presence of severe AMD (quadriceps acid maltase concentration, 0.15 mmol/min/g vs normal range of 8.13[underscore]2.06) with ventilatory muscle weakness. The patient was started on a regimen of high-protein dietary therapy (HPDT) in accordance with Slonim et al.[2] Striking improvement ensued[3] followed by several years of clinical stability. His weight, which had fallen from 114 to 96 kg, had slowly increased to 104 kg by February 1991.

In May 1991, the patient experienced mild daytime hypersomnolence. His wife noted rapid sleep onset, snoring, and occasional nocturnal flailing arm movements, but no definite apneas. By August 1991, daytime hypersomnolence had become disabling, and drooling was noted at night.

A sleep study on nasal oxygen (1 to 3 L/min) using standard methodology demonstrated severe OSA (Table 1 and Fig 1). The next night a continuous positive airway pressure trial showed that the addition of 9 cm [H.sub.2]O pressure to the oxygen afforded maximal achievable improvement in respiratory parameters (Table 1) and marked symptomatic relief. Home continuous positive airway pressure and oxygen delivery systems were requisitioned.

However, the next day the patient developed confusion and cyanosis. Physical examination showed no change in previously noted macroglossia, proximal muscle weakness, and diminished bibasilar breath sounds. The lone preintubation blood gas measurement revealed a [PO.sub.2] of 74 mm Hg, [PCO.sub.2] of 102 mm Hg, and a pH of 7.29 on 2 L nasal oxygen.

Nasotracheal intubation was performed and mechanical ventilation was instituted. Further pulmonary deterioration ensued and the patient died on October 7, 1991.

Pathologic Findings

On gross inspection the tongue was enlarged, measuring 14x7x5 cm and weighing 460 g. Sectioning showed that the tongue musculature had disappeared with only fat and fibrous tissue remaining. The upper airway was otherwise normal. The lungs were firm and edematous, weighing approximately 1,200 g each. The diaphragm was gray-white and thin, with few areas of remaining pink muscle. The intercostal, back, and thigh muscles appeared extensively wasted, but the sterno-cleidomastoids were of normal size and color.

Light microscopy showed bilateral extensive necrotizing broncho-pneumonia. There was near total replacement of tongue muscle by fat. The few remaining myofibers appeared atrophic and degenerated (Fig 2). The diaphragm was thin with virtually complete replacement of muscle by fibrous tissue and fat. The intercostals and back muscles demonstrated marked vacuolization with some muscle preservation. The vacuoles contained PAS-positive granules partially digestible with diastase. The sternocleidomastoids showed nearly normal muscle histologic features.

Electron microscopy of several muscles showed b-particle glycogen granules (both free and membrane bound).

DISCUSSION

The obstructive nature of our patient's hypopneas was demonstrated by simultaneous airflow and intercostal electromyogram recordings (Fig 1). Unfortunately, he required intubation within 48 h of the diagnosis of OSA and never again was able to sustain independent ventilation. Therefore, we were unable to definitively identify the site of obstruction. Nevertheless, the near-total replacement of tongue musculature by fibrofatty tissue, combined with macroglossia, provide a logical explanation for obstruction, particularly in the absence of alternative sites of upper airway narrowing at autopsy.

A somewhat analogous mechanism contributes to the development of OSA in several other disorders, frequently in combination with defects in respiratory control, obesity, and multiple upper airway abnormalities. In myxedema, mucopolysaccharide deposition and protein extravasation into the tissues of the tongue and pharynx may constrict the upper airway and induce a relative genioglossal hypotonia.[4] Some acromegalics exhibit macroglossia and laryngeal narrowing that obliterate the upper airway during sleep, causing OSA.[5] These changes reflect hyperplasia and an accumulation of upper airway tissue water due to chronically elevated growth hormone levels.[6] The syndromes of Hurler and Hunter also predispose to OSA via a complex constellation of progressive upper airway glycosaminoglycan deposition, craniofacial deformities, abnormal tracheal, epiglottic, and cervical structures, and copious secretions.[7,8] Lastly, amyloidosis may rarely produce OSA via massive macroglossia secondary to amyloid infiltration.[9] Our patient's tongue was similarly large and hypotonic; moreover, his lingual fatty metamorphosis provided a unique additional pathophysiologic pathway to OSA.

The occurrence of OSA in an adult patient with AMD is exceedingly rare. True macroglossia, common in infantile patients, appears to be virtually unknown in affected adults, with only one case previously reported.[10] We were likewise able to uncover only a single instance of sleep apnea in a adult with AMD, and no detailed clinical description of that apparently solitary episode was provided.[11]

It is unclear why our patient, after a lengthy period of stability on a regimen of HPDT, developed OSA when he did. Although his weight had increased recently, the magnitude of the increment was small, and he remained well below his initial weight prior to commencing HPDT. We were unable to identify an occult centrally acting agent, such as alcohol, that could have altered respiratory control. There was no obvious worsening of long-standing macroglossia, though serial measurements were not made. Perhaps progressive lingual weakness due to fatty change, in conjunction with macroglossia and mild weight gain, reached a critical point at which nocturnal upper airway patency could no longer be defended. This may be especially likely in the presence of global respiratory muscle weakness.[12] In any event, to our knowledge, the development of OSA has not been noted previously as a complication of HPDT in AMD.

In summary, we believe our case represents both a new clinical association (OSA with adult AMD) and an interesting pathophysiologic interaction.

REFERENCES

[1] Vander Walt JD. Swash M, Leake J, Cox EL. The pattern of involvement of adult-onset acid maltase deficiency at autopsy. Muscle Nerve 1987: 10:272-81

[2] Slonim AE, Coleman RA, McElligott MA, Najjar J. Hirschhorn K, Labadie GU, et al. Improvement of muscle function in acid maltase deficiency by high-protein therapy. Neurology 1983; 33:34-8

[3] Margolis ML, Hill AR. Acid maltase deficiency in an adult=mevidence for improvement in respiratory function with high-protein dietary therapy. Am Rev Respir Dis 1986; 134:328-31

[4] Orr WC, Males JL. Imes NK. Myxedema and obstructive sleep apnea. Am J Med 1981; 70:1061-66

[5] Mezon BJ, West P. Maclean JP, Kryger MH. Sleep apnea in acromegaly. Am J Med 1980; 69:615-18

[6] Hart TB, Radow SK. Blackard WG, Tucker SG, Cooper KR. Sleep apnea in active acromegaly. Arch Intern Med 1985; 145:865-66

[7] Shapiro J, Strome M, Crocker AC. Airway obstruction and sleep apnea in Hurler and Hunter syndrome. Ann Otol Rhinol Laryngol 1985; 94:458-61

[8] Malone BN, Whitley CB, Duvall AJ. Belani K, Sibley RK, Ramsay NKC, et al. Resolution of obstructive sleep apnea in Hurler syndrome after bone marrow transplantation. Int J Pediatr Otorhinolaryngol 1988; 15:23-31

[9] Lesser BA, Leeper KV, Conway W. Obstructive sleep apnea in amyloidosis treated with nasal continuous positive airway pressure. Arch Intern Med 1988; 148:2285-87

[10] Hudgson P, Garner-Medwin D, Worsfold M, Pennington RJT, Walton JN. Adult myopathy from glycogen storage disease due to acid maltase deficiency. Brain 1968; 91:435-61

[11] Trend PSJ, Wiles CM, Spencer GT, Morgan-Hughes JA. Lake BD, Patrick AD. Acid maltase deficiency in adults=mdiagnosis and management in five cases. Brain 1985; 108:845-60

[12] Smith PEM, Calverley PMA, Edwards RHT. Hypoxemia during sleep in Duchenne muscular dystrophy. Am Rev Respir Dis 1988; 137:884-88

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