A Young Woman With Distal Upper Extremity Weakness

A 22-year-old woman presented with an 8-year history of progressive muscle weakness and fatigue, particularly in the hand muscles after physical activities; this became severe over the past year. Her estranged father had an ill-defined muscle weakness during his youth that improved with time.

Serum creatine kinase (CK), antinuclear antibodies, thyroid studies, and blood chemistries were normal.

Examination revealed normal cranial nerves without evidence of ptosis, ophthalmoplegia, or eyelid fatigue. There was mild proximal muscle and finger extensor weakness with fatigue on repetitive testing. Reflexes were symmetric 1–2+, and plantar reflexes were flexor. There was no evidence of myotonia or fasciculations. Sensory examination and coordination were normal and symmetrical.

What is the Differential Diagnosis?

Multiple disorders can cause hand weakness. This is accompanied by pain or sensory deficits in cervical spinal canal disease, such as spondylosis, intramedullary tumors, and syringomyelia. Multifocal motor neuropathy frequently starts in the upper extremities but is often associated with fasciculations; the patient also has a characteristic EMG and conduction block in motor nerve conduction tests.

Distal autoimmune myasthenia gravis is a likely possibility in this patient. Although myasthenia gravis usually presents with ptosis and extraocular and proximal muscle weakness, some patients could manifest with distal weakness. They have the characteristic decremental response on a repetitive nerve stimulation test, and usually have elevated acetylcholine antibody titers or muscle-specific protein kinase (MuSK) antibodies.

Slow-channel myasthenic syndrome (SCMS) is a hereditary, postsynaptic disease of neuromuscular transmission that manifests in weakness of the finger extensors with mild extraocular muscle weakness and ptosis. An afterresponse or afterdischarge is seen after the initial compound muscle action potential during routine motor nerve conduction studies and during the repetitive stimulation test, and there is also a decrement of the CMAP amplitude during this test. Acetylcholine receptor and MuSK antibodies are negative. Edrophonium test may show mild improvement. These patients usually have DNA mutations of the acetylcholine receptor subunit gene.

SCMS can present in adolescence or later in life, whereas most other congenital or hereditary myasthenic syndromes usually start in infancy ( Table 77-1 ). ( Table 77-2 lists the differential diagnosis of the congenital myasthenic syndromes.) SCMS has an autosomal-dominant inheritance, but there is not always a positive family history. A hereditary condition was possible in this patient due to her father’s transient childhood weakness, and thus SCMS should be included in the differential diagnosis.

Table 77-1

Classification of Congenital Myasthenic Syndromes

Reprinted from Oh S. Treatment and management of disorders of neuromuscular junction. In: Bertorni TE, ed. Neuromuscular Disorders: Treatment and Management . Amsterdam, Netherlands: Elsevier; 2022:477. Chapter 19.

Presynaptic Conditions
Congenital caused by choline acetyltransferase (ChAT) deficiency (also referred to as congenital myasthenic syndrome associated with episodic apnea)
Congenital myasthenia with paucity of synaptic vesicles
Congenital myasthenia with quantal release deficiency
Episodic ataxia with myasthenic weakness
Postsynaptic Conditions
Synthetic defect, AChendplate deficiency
Slow-channel congenital myasthenic syndrome
Fast-channel congenital myasthenic syndrome
Receptor deficiency due to mutations in acetylcholine receptor genes
Receptor deficiency due to mutations in rapsyn
MuSK deficiencyDOK7 (limb-girdle weakness)Plectin deficiencyDOK deficiencyGlycosylation deficiency (limb-girdle weakness)

MuSK , Muscle-specific protein kinase.

Table 77-2

Differential Diagnosis of Congenital Myasthenic Syndromes

Reprinted with permission from Engel A. Congenital myasthenic syndromes. In: Katirji B, Kaminski H, Preston D, et al., eds. Neuromuscular Disorders in Clinical Practice . Boston, MA: Butterworth-Heimemann; 2002:955.

Neonatal Period, Infancy, Childhood
Spinal muscular atrophy
Congenital myopathies (central core disease, nemaline myopathy, myotubular myopathy)
Congenital muscular dystrophies
Infantile myotonic dystrophy
Mitochondrial myopathy
Brainstem anomaly
Möbius syndrome
Infantile botulism
Seropositive and seronegative autoimmune myasthenia gravis ^a
Older Patients
Motor neuron disease
Radial nerve palsy ^b
Peripheral neuropathy ^b
Limb-girdle or facioscapulohumeral muscular dystrophy
Mitochondrial myopathy
Chronic fatigue syndrome
Seropositive and seronegative autoimmune myasthenia gravis

a Not reported in the first year of life.

b This diagnosis has been made in some cases of the slow-channel congenital myasthenic syndromes.

Distal muscular dystrophy , particularly the Welander type, is an autosomal-dominant disease that is slowly progressive and not fluctuating. Patients do not have a positive edrophonium test or a decremental response on repetitive stimulation testing. The serum CK is mildly elevated, and muscle biopsy shows characteristic dystrophic changes and rimmed vacuoles.

Myotonic dystrophy can manifest with ptosis and distal extremity weakness; patients also have facial or neck flexor weakness with myotonia demonstrated clinically or by EMG.

Adult onset debranching enzyme deficiency is an autosomal-recessive glycogen storage disease that manifests with distal weakness, but patients usually also have an elevated serum CK and characteristic muscle biopsy showing glycogen accumulation.

Sporadic inclusion body myositis starts in mid-life or later. Patients have predominantly distal lower extremity and upper extremity weakness with prominent quadriceps weakness, elevated serum CK, and a characteristic muscle biopsy demonstrating rimmed vacuoles and inclusion bodies. Familial inclusion body myopathy also shows distal muscle weakness presenting in younger persons but is predominantly in the lower extremities, sparing the quadriceps muscles.

Myofibrillar myopathies are in a heterogeneous group that manifests with distal upper extremity weakness or cardiomyopathy. The serum CK is mildly elevated, and muscle biopsies show characteristic hyaline cytoplasmic inclusions with desmin accumulation.

Nephrotic calcinosis is an autosomal-recessive lysosomal storage myopathy that produces distal hand weakness and renal failure. The biopsy shows a vacuolar myopathy.

Oculopharyngodistal myopathy is characterized by oculopharyngeal and distal upper extremity and lower extremity weakness.

Based on These Possibilities, What Tests Should Be Done?

The patient’s acetylcholine receptor antibodies were normal. MuSK antibodies were not tested. FANA, thyroid function tests, and serum chemistry profile were normal.

Edrophonium test produced mild improvement of the finger extensor weakness ( Fig. 77-1 ).

An EMG Test was Performed

What were the EMG Findings?

Motor Nerve Studies

Nerve and Site	Latency (ms)	Amplitude (mV)	Conduction Velocity (m/s)
Median Nerve L.	Normal ≤ 4.2	Normal ≥ 6	Normal ≥ 50
Wrist	3.3	10	–
Elbow	7.1	9	57

Ulnar Nerve L.	Normal ≤ 3.6	Normal ≥ 8	Normal ≥ 50
Wrist	3.2	6	–
Below elbow	6.4	6	58

F-Wave Studies

Nerve	Latency (ms)	Normal Latency ≤ (ms)
Median nerve L.	27.3	30
Ulnar nerve L.	27.8	30

Sensory Nerve Studies

Nerve	Onset Latency (ms)	Normal Onset Latency ≤ (ms)	Peak Latency (ms)	Normal Peak Latency ≤ (ms)	Amp (μV)	Normal Amp ≥ (μV)	Conduction Velocity (m/s)	Normal Conduction Velocity ≥ (m/s)
Median nerve L.	2.2	2.6	2.7	3.1	38	20	59	50
Ulnar nerve L.	2.2	2.6	2.7	3.1	29	13	55	50

Repetitive Stimulation of Ulnar Nerve L.

Potential Number	Amp (mV)	Amp Decrement (%)	Area Decrement (%)
Before Exercise
1	6.24	0	0
2	6.19	4	3
3	6.17	6	9
4	6.17	6	9
5	6.17	6	9
Posttetanic
1	6.05	0	0
2	6.02	1	0
3	5.65	2	4
4	5.65	2	6
5	5.67	2	7
1 min Postexercise
1	6.36	0	0
2	5.99	5	2
3	5.70	9	5
4	5.70	9	7
5	5.69	9	7
2 min Postexercise
1	6.60	0	0
2	6.24	4	2
3	6.09	6	3
4	6.02	5	5
5	6.01	5	5

Repetitive Stimulation of Accessory Nerve L.

Potential Number	Amp (mV)	Amp Decrement (%)	Area Decrement (%)
Before Exercise
1	15.96	0	0
2	15.65	4	0
3	15.51	6	5
4	14.45	7	7
5	15.39	8	9
Posttetanic
1	15.55	0	0
2	15.41	6	2
3	15.39	6	4
4	15.33	7	6
5	15.31	7	6
1 min Postexercise
1	15.36	0	0
2	14.99	5	4
3	14.73	9	7
4	14.71	9	9
5	14.70	9	9
2 min Postexercise
1	15.55	0	0
2	15.18	5	3
3	15.17	5	5
4	14.91	9	8
5	14.89	9	8