Adult phosphorylaseb kinase deficiency

Adult Phosphorylase b &nase Deficiency Paula R. Clemens, MD, Masahiko Yamamoto, MD, and Andrew G. Engel, MD

Phosphorylase b kinase deficiency affecting muscle has been observed infrequently in children with weakness and hepatomegaly, and in 2 adults with cramps on exertion. We observed 2 additional adults with phosphorylase b kinase deficiency: Patienc 1, aged 58,had progressive, predominantly distal weakness since age 46 but no cramps on exertion; Patient 2, aged 26, had cramps on exertion since age 6 but no weakness. Lactate production on ischemic exercise was impaired only in Patient 1. The serum creatine kinase level was elevated in both. Muscle specimens showed focal glycogen excess in both, and a necrotizing myopathy and mild denervation atrophy in Patient 1. Muscle phosphorylase b kinase activity was 0.570 and 8.9% of the lowest control value in Patients 1 and 2, respectively; erythrocyte phosphorylase b kinase activity was normal in both; liver phosphorylase b kinase activity, measured in Patient 1, was also normal. Other glycolytic enzymes in muscle were preserved in both. Clemens PR, Yamamoto M, Engel AG. Adult phosphorylase b kinase deficiency. Ann Neurol 1990;28:529-538

Phosphorylase b kinase (PBK) plays an important dual role in regulating glycogen metabolism. First it initiates glycogenolysis by converting phosphorylase from an inactive b to an active a form [l]. Second, together with other protein kinases, it inhibits glycogen synthesis by converting glycogen synthase from an active u to an inactive b form {2}. According to current knowledge, PBK is composed of four subunits in a stoichiometry of a&4y&+ The y subunits are catalytic, the a and p subunits are regulatory, and the 6 subunits are identical with the calciumbinding protein, calmodulin. An a’ isozyme of the a subunit is found in heart and slow-twitch muscle fibers [3}. PBK can be activated by two mechanisms in vivo: The first is a reaction cascade that begins with the activation of adenylate cyclase via G proteins by epinephrine in muscle, and by epinephrine or glucagon in liver; adenylate cyclase generates cyclic AMP (CAMP), which activates CAMP-dependent protein kinase; and this kinase activates PBK by phosphorylating the a and p subunits of the enzyme. In the second mechanism, calcium activates PBK by binding to its 6 subunits [3]. X-linked recessive and X-linked dominant PBK deficiencies have been described in the mouse and an autosomal recessive PBK deficiency exists in the rat {4, 51 (see Discussion). The human PBK deficiency syndromes observed to date are also heterogeneous. Most cases have been infants or children. A fatal infantile cardiac type of undetermined inheritance, an X-linked recessive hepatic type, and a muscle-liver type, which ifi some cases is autosomal recessive, have emerged thus far (cases cited in the Discussion).

From the Department of Neurology and rhe Neuromuscular Research Laboratory, Mayo Clinic and Mayo Foundation, Rochester, MN.

Two adults with muscle PBK deficiency have been described to date. The first, reported by Abarbanel and colleagues, presented with exercise-induced calf pain and pigmenturia at age 35 and had glycogen excess in muscle 161. The second, briefly reported by Servidei and associates, was a 35-year-old man with exercise-induced cramps [7]. We here report 2 further adults with muscle PBK deficiency, but with disparate clinical features. The first patient had progressive muscle weakness that began in the fifth decade of life. The second patient had exercise-induced muscle symptoms since childhood but no permanent muscle weakness. Clinical Data Patient 1 A 58-year-old man had had difficulty walking on his heels since age 46. By the age of 52, he had increasing difficulty walking on a level surface, climbing stairs, rising from sitting, or stepping into a tub. Even though he had been physically active and an avid tennis player, he never had muscle aches, cramps, contractures, or pigmenturia. However, since his teens he perspired excessively and felt light-headed when he exercised while fasting. These symptoms were prevented or rapidly reversed by carbohydrate ingestion. At the age of 57, an elevated serum creatine kinase (CK) level prompted therapy with 30 mg of prednisone per day for 3 months. The serum CK level fell but not to normal and the patient’s weakness continued to progress. Prednisone was gradually discontinued over the next 6 months. There was no history of muscle disease in the parents, two half-siblings (52 and 56 years old), or three children (two sons, 19 and 29 years old, and one daughter, 27 years old). Examination at the age of 58 showed a reduced bulk of

Received Feb 6, 1990, and in revised form Apr 23. Accepted for publicarion Apr 23, 1990. Address correspondence to Dr Engel, Department of Neurology, Mayo Clinic, Rochester, MN 55905.

Copyright B 1990 by the American Neurological Association 529

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