Although there is considerable variation in the
age of onset, the severity and progression rate of symptoms and the clinical
phenotype of all forms of CMT are generally similar. A minority of patients
present at birth with hypotonia or later with motor delay. However, the
majority of patients present later in life, usually within the first 2
decades. The most common complaint is distal leg weakness, which manifests
as frequent tripping and muscle atrophy. Hand involvement follows in most
cases. Pregnancy may exacerbate a preexisting weakness in 50% of patients
with early-onset disease. The exacerbation is transient in one third of
women, but unfortunately is progressive in the other two thirds.
Cardiomyopathy and cardiac conduction abnormalities are seen occasionally.
Clinical features may include foot dropping, pes cavus deformity, muscle
cramping, steppage or equine gait, “champagne bottle” or stork legs,
hammer toes, clawhand, and diminished or absent deep tendon reflexes. Pain
and temperature sensation are normal. The diaphragm, phrenic nerve, and vocal
cords are occasionally involved. Life expectancy usually is not affected,
and confinement to the wheelchair is rare.
Charcot-Marie-Tooth Disease Type I
Type IA: Approximately 90% of CMT I patients belong to this group. They all have
in common a partial duplication of the PMP22 gene: clinical symptoms appear
in the first or early in the second decade of life. In infants and children,
the disease presents with patients walking on their toes and severe
tightness of the heel cord. Occasionally, these patients are born with
clubfoot. Gait anomalies, foot deformities, and loss of balance are the main
complaints in these patients and the reason they seek medical help. Distal
leg weakness predominantly affects the dorsiflexor muscles (innervated by
the peroneal nerve), which may result in frequent tripping over objects
lying on the floor. Accordingly, difficulties or inability to walk on the
heels usually is one of the early signs of the disease. As the disease
progresses, weakness becomes more pronounced and results in foot drops with
each step, forcing the patient to flex the hips more, which leads to the
steppage or equine gait. The imbalance between intrinsic and extrinsic foot
muscles may result in the formation of pes cavus. Peroneal muscle atrophy
may lead to inverted “champagne bottle" or stork legs, but may be masked by a
thicker layer of subcutaneous fat. At this stage, patients often complain
about leg muscle cramps and lumbar back pain. Later, most often the hands
also start to show signs of weakness and atrophy that may result in
clawhand deformity (marked extension of the fingers in the
metacarpophalangeal joints, while the distal and proximal interphalangeal
joints are flexed) with serious handicapping in daily life. Involvement of
the hand does not appear to be related to the degree of leg weakness.
Decreased vibratory sense is common, and mild sensory loss in a stocking
distribution is not uncommon. Enlargement of the nerves to the point that
they can be seen or palpated occurs in about one fourth of patients and is
more common in men, but it seems not to be related to the severity of the
disease. Approximately 40% of patients have a tremor, which usually
starts in the fourth decade of life. Symptoms of hip dysplasia usually begin
in adolescence. Pulmonary symptoms have been reported in CMT patients.
Spirometry values and static lung volumes are usually within normal limits,
but testing of the inspiratory and expiratory muscles reveals a
significantly decreased function.
Roussy-Levy Syndrome: This phenotypic variant has some features in
common with Friedreich Ataxia and presents with pes cavus, distal limb
weakness, areflexia, tremor in the hands, and distal sensory loss with
ataxia. Genetic analysis in these patients has shown a duplication of the
Davidenkow Syndrome (Scapuloperoneal Atrophy): Scapuloperoneal muscle
atrophy with pes cavus, areflexia, and distal sensory loss. Motor nerve
conduction velocities are decreased, and hypertrophic changes of the nerves
are present. These patients have the partial duplication of 17p11.2,
supporting the fact that this is another variant of CMT IA.
Type IB: This group accounts for the residual 10% of CMT I patients, which share a
point mutation in the MPZ gene. In comparison with CMT IA, symptoms start
much earlier with delayed ability to walk, proximal leg weakness, and slower
nerve conduction velocities than in CMT IA. Sural nerve biopsy reveals the
demyelinating process with onion bulb formation.
Dejerine-Sottas Syndrome: Characterized by onset in infancy or
early childhood with delayed motor development, rapid progression, and often
profound nerve hypertrophy. This form is most often caused by either de novo
point mutations in the PMP22 or MPZ gene.
Congenital Hypomyelination: Infantile hypotonia secondary to distal
muscle weakness, areflexia, and very slow nerve conduction velocities. The
combination with joint contractures and Arthrogryposis Multiplex has
been described. Sural nerve biopsy reveals hypomyelination without signs of
active myelin breakdown. This form is caused by mutations in the MPZ gene.
Charcot-Marie-Tooth Disease Type II
This genetically heterogenous form of CMT, also called the neuronal type of CMT, is
clinically similar to CMT I (with the same wide variability). However, the
age of onset is more variable and in general is later than in CMT I. Motor
nerve conduction velocities are normal or only slightly diminished, the
nerves show no signs of hypertrophy, and nerve biopsy lacks the typical
onion bulb formation seen in CMT I. Distal leg weakness with muscular
atrophy, pes cavus deformity, and steppage gait are similar to CMT I, while
the hand muscles are less often affected and deep tendon reflexes are
intact. Genetically, several different mutations have been identified and
mapped to chromosomes 1, 3, and 7.
CMTX/X-Linked HMSN: In approximately 90%, CMTX is inherited in an X-linked dominant
transmission; the remaining 10% show X-linked recessive transmission. The
clinical signs are similar to those of CMT IA, but males are more severely
affected than females. The significantly decreased nerve conduction velocity
supports a demyelinating process.