Fred (not his real name) is a 53-year-old man of German and Russian ancestry who lives in New York state.

He's come to the MDA clinic because of increasing weakness of his thigh muscles and some weakness of his grip over the last several years. He has no obvious muscle atrophy.

He gets out of a chair with difficulty, using the chair arms for support, and shakes hands weakly. His gait is somewhat halting, and he reports he occasionally uses a cane or scooter to cover distances. He picks up his feet and doesn't trip over them.

He says his mother, now deceased, had severe weakness of her proximal (close to the trunk) leg muscles, and couldn't easily rise from low furniture. She was very overweight, however, and he attributed her mobility problems to that. His father died young of tuberculosis. His half-brothers don't appear to have been affected by any neuromuscular condition.

Fred says he's recently had great difficulty with stairs, particularly ladders, which he sometimes must use in his job on construction sites. However, he remembers that 15 years ago when he was playing with his young son on the floor, he had problems getting up and had to hold onto furniture.

He developed cataracts in both eyes in his 30s but only recently had them removed, after they began to interfere with his vision.

SUSPECTS

Fred probably has a neuromuscular junction disease such as myasthenia gravis (MG) or Lambert-Eaton syndrome (LEMS) or a muscle disease. Diseases of the peripheral nerves generally cause more atrophy and more weakness of the distal (far from the trunk) muscles than he has. A motor neuron disease like ALS or SMA is possible.

His mother's symptoms indicate a possible hereditary disease.

	AMD acid maltase deficiency (Pompe's disease) ALS amyotrophic lateral sclerosis DM dermatomyositis IBM inclusion-body myositis LEMS Lambert-Eaton myasthenic syndrome LGMD limb-girdle muscular dystrophy	MG myasthenia gravis MMD1 type 1 myotonic dystrophy MMD2 type 2 myotonic dystrophy PM polymyositis SMA spinal muscular atrophy TM thyroid myopathy

2. THE SEARCH GOES ON...

EXAMINATION

Fred's muscle strength is normal except for a score of 4+ in his neck muscles, arm-extending muscles, hip-flexing muscles, knee-extending muscles, and toe flexors and extensors. His grip is slightly weak at 4+. Strength doesn't decrease or increase with repeated trials. (See explanation of these ratings.)

He's unable to rise from the floor or from a low chair without using his hands. He's unable to do a sit-up with his arms behind his head.

Several areas seem normal: touch and pain sensation, skin condition, twitches (fasciculations), obvious cardiac or respiratory problems.

His deep tendon reflexes are normal except at the ankles, where they're slightly decreased, at 1+.

He says he's not overly sleepy during the day, doesn't fatigue easily with exercise and doesn't believe he has any special problems with his memory or intellect. Examiner notices Fred has enlarged calves and frontal balding.

SUSPECTS

NOT LIKELY: Peripheral nerve disease still looks unlikely, since reflexes aren't decreased.

Neuromuscular junction disorders usually worsen with repeated tests of strength, although LEMS usually improves. This patient stayed the same, nearly ruling out these disorders.

POSSIBLE: Adult-onset spinal muscular atrophy (SMA), which involves proximal weakness, or amyotrophic lateral sclerosis (ALS). But both usually show some fasciculations, and ALS usually shows brisk, overactive reflexes.

MOST LIKELY: A muscle disease. Good candidates are:

• inclusion-body myositis (IBM), an acquired muscle disease that usually affects men in Fred's age group

• inflammatory muscle diseases polymyositis (PM) and dermatomyositis (DM), though pain is often involved with these and a skin rash is common with DM

• adult-onset acid maltase deficiency (AMD, or Pompe's disease), caused by a metabolic problem in which glycogen (stored sugar) builds up in muscle cells

• late-onset muscular dystrophy, such as limb-girdle (LGMD) or myotonic dystrophy (MMD) (his distribution of weakness is most typical of type 2 MMD, but type 1 is more common)

• thyroid myopathy (TM), which can sometimes cause fairly severe weakness.

3. THE SEARCH GOES ON...

TESTS

Creatine kinase (CK) level is normal.

Thyroid function is normal.

Blood sugar is somewhat high.

Serum antibodies often found in PM and DM are absent.

Nerve impulses are conducted at a normal speed and with normal strength.

SUSPECTS

RULED OUT: The normal CK level suggests this isn't PM or DM or LGMD; lack of antibodies suggests it isn't PM or DM. TM is ruled out by the normal thyroid tests. Nerve tests rule out ALS and SMA.

LESS LIKELY: Fred's CK is low for AMD, but this disease sometimes shows myotonia.

NEW FRONT-RUNNER: The finding of myotonia — unlikely in the other diseases being considered — tips the balance toward MMD.

4. THE SEARCH IS NARROWED ...

DNA TEST

Type 1 MMD: negative

MUSCLE BIOPSY

Sample taken from Fred's thigh muscle shows evidence of muscle degeneration typical of a moderately severe muscular dystrophy or acquired muscle disease. It shows no evidence of glycogen accumulation.

SUSPECTS

RULED OUT: The lack of glycogen accumulation eliminates AMD. The DNA test eliminates MMD1.

POSSIBLE: IBM is still possible, though it usually doesn't feature myotonia.

The tentative diagnosis is type 2 MMD.

5. AND THE CULPRIT IS ..

DNA TEST

Type 2 MMD: positive

DIAGNOSIS

Type 2 MMD

The myotonia, cataracts, high blood sugar, calf enlargement, family history and balding can all be explained by this diagnosis.

This is a genetic disease, inherited in a dominant fashion on chromosome 3. (A flawed gene from one parent can cause the disorder.) It appears to be particularly common in people of German and Eastern European ancestry. It's likely that Fred's mother also had type 2 MMD.

Fred's 18-year-old son has a 50 percent chance of having inherited the chromosome 3 genetic mutation from his father. The young man shows no signs of the disease, and the family and physician decide to wait until he is older to discuss genetic and other testing options with him.

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