Clinical Features

The incidence of Bell’s palsy is 2.7 per 100,000 below the age of 10 years, and 10.1 per 100,000 during the second decade of life [Katusik et al., 1986]. Female and male incidence is equal. Ear pain near the mastoid process is the first manifestation of impending facial nerve involvement half of the time. Unilateral inability to close the eyelid and maintain normal facial movement is the initial indication of motor involvement. Facial weakness develops rapidly over several hours to 3 days, resulting in paresis to complete paralysis. Bell’s palsy commonly follows an upper respiratory tract infection, indicating possible postinfectious demyelination. Drinking and eating are impaired because of the inability to close the mouth on the involved side. Depending on the site of facial nerve involvement (see Figure 89-2 and Table 89-1), lacrimation may be decreased and taste distorted.

Taste sensation is evaluated by applying solutions of sugar and salt alternately to the anterior edge of the tongue on the involved side while holding the tongue with a piece of gauze. The tongue should not be retracted during the examination because the solutions will intermix. Lacrimation may be reduced on the ipsilateral side. However, if the parasympathetic pathways of lacrimation are intact, excessive tearing can occur from corneal irritation. Diminished lacrimation may be determined by hooking filter paper over both lower eyelid margins and observing decreased wetting of the paper on the involved side over 5 minutes (Schirmer test). Stapedius nerve function is evaluated by audiologic study.

The differential diagnosis of facial paralysis includes trauma, acute and chronic infections of the inner ear, herpes simplex infection, herpes zoster, Mycoplasma pneumoniae infection [Klar et al., 1985], Epstein–Barr virus infection [Andersson and Sterner, 1985], and Lyme disease (Borrelia spp. infection) (Box 89-1). Hypertension may be responsible for an acute facial paresis resembling Bell’s palsy [Lloyd et al., 1966]. Melkersson–Rosenthal and Möbius’ syndromes have facial paralysis. Guillain–Barré syndrome, motor neuron disorders, myasthenia gravis, various myopathies, leprosy, and Tangier disease may cause facial paresis. The Melkersson–Rosenthal syndrome is marked by orofacial edema, facial nerve palsy, fissured tongue, and epithelial noncaseating granulomas with perivascular infiltrates [Cousin et al., 1998; Kaminagukura and Jorge, 2009].

Box 89-1 Facial Weakness in Childhood

Congenital, Structural

Chiari malformation

Depressor anguli oris muscle absence (cardiofacial syndrome)

Inner ear and/or facial nerve malformations

Möbius’ syndrome

Syringobulbia

Genetic

Facioscapulohumeral dystrophy

Familial cranial neuropathy (recurrent)

Fazio–Londe disease

Myasthenia gravis (nonimmune-mediated)

Myotonic dystrophy

Nemaline myopathy

Infectious, Inflammatory

Basilar meningitis

Bell’s palsy

Epstein–Barr infection (infectious mononucleosis)

Guillain–Barré syndrome

Miller–Fisher syndrome

Mycoplasma pneumoniae infection

Lyme disease (Borrelia spp. infection)

Otitis media and mastoiditis

Parotitis

Poliomyelitis

Ramsay Hunt syndrome (herpes zoster)

Sarcoidosis

Trichinosis

Tuberculosis

Trauma, Nerve Compression

Forceps pressure during delivery

Cleidocranial dysostosis

Histiocytosis X

Hyperostosis cranialis interna

Increased intracranial pressure

Petrous bone fracture

Pressure from maternal sacrum

Metabolic Conditions

Hyperparathyroidism

Hypothyroidism

Idiopathic infantile hypercalcemia

Osteopetrosis

Neoplasms

Brainstem glioma

Parotid gland tumor

Vascular

Arterial hypertension

Vascular syndromes of the cranial nerves

Other

Idiopathic cranial neuropathy

Melkersson–Rosenthal syndrome

Multiple sclerosis

Myasthenia gravis (immune-mediated)

Myasthenia gravis (transient neonatal)

In rare circumstances, Bell’s palsy can present bilaterally in children, although one side is usually more involved than the other. The side more affected usually is paralyzed first and the side less involved by the next day. Bilateral facial nerve palsy is often associated with Guillain–Barré syndrome.

Bilateral, congenital facial paralysis, usually in conjunction with ophthalmoplegia involving cranial nerve VI, presents in the newborn as Möbius’ syndrome. The condition is the result of aplasia or hypoplasia of cranial nerves and nuclei VI and VII [Jaradeh et al., 1996]. Muscles innervated by other cranial nerves may be involved. Arthrogryposis may be present. Mental retardation may be diagnosed later. Möbius’ syndrome may be sporadic or inherited as a dominant condition linked to chromosomes 13q12.2–13 or 3q [Kremer et al., 1996; Nishikawa et al., 1997]. Differential diagnosis includes traumatic delivery with skull fracture and injury to the nerve in the facial canal, sacral pressure on the facial nerve during delivery, or pressure over the parotid area from forceps application with nerve compression. Möbius’ syndrome may be related in some instances to maternal ingestion of ergotamine in early pregnancy [Smets et al., 2004].

Simple asymmetry of facial expression when infants and children are crying is common. A rare syndrome, the cardiofacial syndrome, referred to as Cayler’s syndrome, is due to congenital hypoplasia of the depressor anguli oris causing the asymmetric crying facies syndrome. Unilateral partial lower facial weakness is noted in infants when smiling or crying. The syndrome is associated with congenital heart disease [Caksen et al., 1996; Cayler et al., 1971; Nelson and Eng, 1972; Punal et al., 2001]. Anomalies of the head and neck, heart, skeleton, genitourinary tract, and CNS accompany the syndrome [Lin et al., 1997]. Cardiofacial syndrome links to chromosome 22q11.2. Variations include one infant without cardiac involvement and another with hypoparathyroidism [Giannotti and Mingarelli, 1994; Lindsay et al., 1995; Stewart and Smith, 1997]. Frameshift mutation of the EYA1 gene has been described [Shimasaki et al., 2004]. Microduplication of 22q11.2 is associated with velocardiofacial syndrome, DiGeorge’s syndrome, conotruncal anomaly face syndrome, and in some but not all children with Caylor’s cardiofacial syndrome [Cotter et al., 2005]. The majority of children with asymmetrical crying facies are normal.

Laboratory Findings

Uncomplicated facial palsy that resolves relatively quickly does not need detailed evaluation. Palsy that persists or seems atypical requires study. Evaluation for infection is appropriate, but peripheral leukocyte and differential counts and erythrocyte sedimentation rate are usually normal. Cerebrospinal fluid (CSF) studies may show pleocytosis and blood–brain barrier alterations in Lyme disease (Borrelia spp. infection) [Roberg et al., 1991]. Imaging of the cranium is performed to exclude skull fracture, osteomyelitis, mastoiditis, increased intracranial pressure, calcification, and osteopetrosis. Magnetic resonance imaging (MRI) often reveals gadolinium enhancement of the facial nerve in typical cases of Bell’s palsy. This has been used in adults to predict the outcome of acute facial nerve palsy during the first few days after onset of symptoms [Kress et al., 2004]. The time to recovery from onset may increase from 6 to 14 weeks if enhancement on postcontrast images is present [Yetiser et al., 2003]. MRI can be used in children to find rare tumors invading the facial nerve [Koerbel et al., 2003]. Small lesions inside the temporal bone and at the cerebellopontine angle can be detected using gadolinium-enhanced MRI [Becelli et al., 2003]. Electrodiagnostic techniques may be useful in assessing the severity of facial nerve involvement and predicting the outcome. These studies include determination of nerve conduction velocity [Langworth and Taverner, 1963], detection of the level or threshold of response to stimulation [Campbell et al., 1962; Devi et al., 1978], nerve conduction latencies, and electrical stimulation of the tongue [Peiris and Miles, 1965]. Serial studies may be helpful [Fisch, 1984]. Nerve degeneration can be detected electrically by 72 hours after onset of paralysis.

Because Bell’s palsy may be a component of a more widespread disease affecting other cranial and peripheral nerves, obtaining a complete electromyographic evaluation and extremity nerve conduction velocities is sometimes helpful [Bueri et al., 1984].

Treatment and Prognosis

The prognosis for recovery in children is good [Singhi and Jain, 2003]. Most children do not need drug therapy [Salman and MacGregor, 2001]. A number of drugs have been used, particularly steroids. Surgical decompression has been recommended in some patients when progressive paralysis and thus nerve degeneration occur [Jenkins et al., 1985]. Prednisone is the most widely used drug; it is given in high dosage for 1 week, followed by slow withdrawal of the drug in the second week. It should be started within 1 week of disease onset. The degree to which steroid therapy can alter the natural history of Bell’s palsy is unknown, although it appears to be more helpful in completely paralyzed than paretic individuals [Wolf et al., 1978]. Most children recover completely without treatment. Recovery usually begins within 2–4 weeks, reaching its maximum within 6–12 months. In meta-analyses comparing steroids to antiviral treatment, usually acyclovir, there is no added advantage in adding antiviral treatment to steroid treatment [Quant et al., 2009; Sullivan et al., 2007]. Wetting solutions to maintain corneal moisture and an eye patch for protection may be needed when the child cannot close the eye.

Pathology

Demyelination and mononuclear cell infiltration of peripheral nerve may be found on nerve biopsy in AIDP. Varying degrees of edema, endoneurial lymphocytic cell infiltration, and segmental demyelination occur (Figure 89-5). Macrophage invasion of Schwann cells can be seen ultrastructurally [Brechenmacher et al., 1987]. Spinal roots and proximal and distal nerves display focal and perivenular lymphocytes and macrophages [Hall et al., 1992]. Complement fixing antibodies to peripheral nerve myelin may be demonstrated in some cases [Koski et al., 1987]. Children with previous diarrhea are more likely to have autoantibodies [Nishimoto et al., 2008]. Axonal degeneration is present in AMAN and AMSAN, with antibodies to gangliosides on the axolemma that target macrophages to invade the axon at the node of Ranvier, producing axonal degeneration and subsequent muscle weakness [Hughes and Cornblath, 2005; Uncini and Yuki, 2009]. In AMAN, antibodies against GM1, GM1b, GD1a, and GalNAc-G1a have been found in children [Nishimoto et al., 2008]. Antibodies to GalNaccGd1a are found in AMSAN and to GQ1b in Miller Fisher syndrome [Hughes and Cornblath, 2005]. CSF protein is often elevated after the first week, usually accompanied by a lack of inflammatory cellular response – often with fewer than 10 lymphocytes/mm³.

Fig. 89-5 Sural nerve biopsy from a 14-year-old boy with acute inflammatory demyelinating polyradiculoneuropathy.

A, Part of a nerve fascicle demonstrating demyelinating nerve fibers (arrows) and perivascular infiltration (arrow tip) (×1180). B, Perivenular lymphocytic infiltrate (arrow) (×1560).

Clinical Characteristics

The overall incidence of AIDP is 1–2 per 100,000 each year; in the population younger than 18 years, the incidence is 0.8 per 100,000 each year [Beghi et al., 1985]. The incidence rate for males is 1.5 times that for females [Koobatian et al., 1992]. Muscle pain may be the initial manifestation of the disease in children, involving the anterior and posterior thighs, buttocks, and lower back [Ropper and Shahani, 1984]. Pain and paresthesias after infection are quickly followed by symmetric, progressive weakness of extremity and facial muscles. Bladder dysfunction, mental alterations, headache, ataxia, and meningismus may be accompanying features. Tendon reflexes are diminished or lost. The disease may progress for days to several weeks (median of 7 days) before plateauing [Korinthenberg et al., 2007], and then improves over a period of months. Weakness may proceed rapidly with complete paralysis, including bulbar paralysis, developing within 24 hours of onset. Ventilatory support may be necessary, even early in the course of the illness. Eighty percent of patients make an excellent recovery.

Autonomic involvement may produce blurred vision, cramping abdominal pain, postural hypotension, hypertension, cardiac arrhythmia, and bladder and bowel incontinence. These symptoms may occur transiently in the course of predominantly motor and sensory involvement, and usually do not cause serious morbidity in children; in adults, however, cardiac arrhythmias and blood pressure alterations may be life-threatening. Hyponatremia may occur due to inappropriate secretion of antidiuretic hormone.

Unusual childhood variants of Guillain–Barré syndrome include:

MRI often reveals gadolinium enhancement of the spinal nerve roots. Electrophysiologic evaluation usually provides evidence of peripheral nerve demyelination, often accompanied by changes indicative of axonal involvement. Distal motor latencies are prolonged to more than 150 percent of normal. Nerve conduction velocities are reduced to below 70 percent of normal. Compound motor action potentials are significantly reduced, with prolonged terminal dispersions, these being the most common electrophysiologic findings in children [Bradshaw and Jones, 1992]. Children younger than 10 years of age have greater slowing of motor nerve conduction velocities than children older than 10. More profound slowing corresponds to high antibody levels against peripheral nerve myelin during the first week of illness [Rudnicki et al., 1992]. In cases where the pathologic change is one of mainly axonal degeneration, nerve conduction studies reveal normal or mildly slow conduction with diminished amplitude of compound muscle action potentials.

The youngest reported patients are neonates. A 4-month-old child presented with advancing hypotonia [Carroll et al., 1977]. Several other children younger than 6 months of age have been reported. The rate of progression, degree of impairment, and time before improvement vary greatly; however, recovery does not continue after 2 years from onset [Ropper, 1986]. Poor prognosis is related to the need for ventilation, and failure to improve after 3 weeks of reaching peak deficit [Winer et al., 1985]. The mortality rate approaches 5 percent in adults but should be negligible in children; 10–15 percent of adults remain permanently disabled [Arnason, 1984].

Management

As the prognosis is usually excellent for spontaneous recovery, the mainstay of treatment is supportive. Mechanical ventilation may be needed, and careful attention to nutritional, fluid, and electrolyte balance is necessary. When paralyzed and ventilated, children are still mentally alert. They need psychologic support from parents and caregivers. The ordeal may be very frightening.

Plasmapheresis may be effective if begun within 7 days of illness onset [French Cooperative Group, 1987; Greenwood et al., 1984; Guillain-Barré Syndrome Study Group, 1985; Osterman et al., 1984; Smith and Hughes, 1992]. If patients lose the ability to walk unaided, have significant reduction in respiratory capacity, or have bulbar insufficiency, plasmapheresis or intravenous immunoglobulin therapy is indicated. Although most plasmapheresis studies have been performed on adults, a study on children demonstrated shortened recovery time in 5 of 6 children aged 5–15 years [Lamont et al., 1991]. A retrospective study showed faster recovery of independent ambulation in 9 children who received plasmapheresis, compared with 14 who did not receive plasmapheresis [Epstein and Sladky, 1990]. Intravenous gamma globulin is more convenient in small children and shortens the course of illness [Kleyweg et al., 1988; Sladky, 2004; Tasdemir et al., 2006]. In adults, intravenous immunoglobulin given during the first week is at least as effective as plasmapheresis and may be of greater efficacy [van der Meché et al., 1992]. There is no documented benefit to using both therapies [Bril et al., 1996; Hughes and Plasma Exchange/Sandoglobin Guillain–Barré Syndrome Trial Group, 1996].

Investigations

Cerebrospinal protein is elevated, with a normal cell count. Slowed conduction velocities, prolonged distal latencies, and temporal dispersion are present electrophysiologically. MRI often reveals gadolinium enhancement of the spinal nerve roots. Sural nerve biopsy, if performed, shows demyelination, remyelination, and usually a T-cell lymphocyte and macrophage inflammatory infiltrate. Onion bulb formation indicates chronicity of the condition (Figure 89-6). Circulating CD4+ and CD25+ T-regulatory lymphocytes are reduced in CIDP patients, and there is increased frequency of genotype GA13–16 of the SH2D2A gene, encoding a T-cell-specific adapter protein [Notturno et al., 2008]. These findings seemingly alter immune responses, predisposing affected individuals to chronic illness.

Fig. 89-6 Sural nerve biopsy from a 5-year-old girl with chronic inflammatory demyelinating polyradiculoneuropathy.

A, Demyelination of two nerve fibers (arrows) with lymphocytes (L) located nearby (×7300). B, Partial demyelination of a nerve fiber surrounded by redundant Schwann cell elements, including excessive basement membrane. This process represents early onion bulb formation, which develops as the disease progresses (×10,000).

Management

Childhood CIDP has been shown to improve with therapy [Colan et al., 1980; Gorson et al., 1997; Nevo et al., 1996; Sladky et al., 1986; Uncini et al., 1991], which most often begins with intravenous immunoglobulin; however, most children respond to corticosteroids, with slow tapering to prevent relapses [Rabie and Nevo, 2009]. In children resistant to oral prednisone or intravenous methylprednisolone and intravenous immunoglobulin, cyclosporine may be of benefit. Two infants and one child responded to treatment without adverse effects. A small group of patients require intense immunosuppression and some require regular intravenous immunoglobulin infusions for a prolonged period.

Pathology

The peripheral nerves in CMT type I are often easily palpated because they are hypertrophied as a result of excessive Schwann cell and fibroblast activity. This creates redundant wrappings of Schwann cell investments around nerve fibers accompanied by excessive collagen deposition, known as onion bulbs [Thomas et al., 1974]. Sural nerve biopsies disclose a loss of myelinated fibers, especially the large myelinated fibers. With advancing age, there is progressive reduction in the myelinated fiber density, an increased number of fibers undergoing demyelination, and increased frequency of onion bulb formations [Low et al., 1978]. In this setting, onion bulb formations are the result of repeated episodes of demyelination and remyelination (Figure 89-7). Some loss of axons is eventually observed, indicating that, although demyelination is predominant, some axonal degeneration is part of the disease process and is responsible for the progression of the weakness and wasting [Nordborg et al., 1984].

Fig. 89-7 Sural nerve biopsy from a 15-year-old girl with hereditary motor and sensory neuropathy type I, the hypertrophic form of Charcot–Marie–Tooth disease.

A, Demyelination and axonal disruption are noted (×17,400.). B, Typical onion bulb formation with a myelinated nerve fiber surrounded by redundant Schwann cell investments, basement laminae, and collagen (×10,100).

Clinical Characteristics

The disease is typically recognized during the first decade of life or in early adolescence, but it may be evident even at birth. A large variation in the age of onset and severity of disease among individuals in the same family has sometimes been observed [Birouk et al., 1997; Hagberg and Lyon, 1981]. Early onset, although uncommon, usually results in greater disability later in life than that seen in individuals with later onset, who are often able to ambulate and work until old age.

The disease presents with distal lower-extremity muscle wasting and weakness accompanied by development of pes cavus. Progressive weakness of the tibialis anterior and peroneal muscles, which are more involved clinically than the tibialis posterior muscle, is associated with the development of the high arch of the foot or pes cavus. The hammer toe deformities occur as the long toe extensors attempt to make up for the foot dorsiflexor (tibialis anterior) atrophy and weakness. Gradual loss of sensation is noted, especially loss of proprioception, which causes unsteady gait in darkness and a positive Romberg sign. Vibration and big toe position sense are both diminished. Tendon reflexes are usually lost early at the ankle and later at the knee. Muscle wasting and weakness slowly spread proximally, so that atrophy of the medial rectus muscle and distal rectus femoris in the quadriceps group becomes apparent. Classically, the leg assumes a storklike appearance, with little motor function remaining, but this is rare in children with CMT type I. As the lower extremities become more involved, atrophy of the hand intrinsic muscles with accompanying weakness is recognized, which leads to difficulty with fine motor skills, including writing. Distal sensory loss soon becomes evident in the upper extremities. Kyphosis and scoliosis develop in about 10 percent of cases. Acquired hip dysplasia occurs in a similar percentage of cases. Variability of expression among families makes it difficult to describe a uniform rate of change. Typically, younger age of clinical recognition and more rapid progression in a parent are associated with similar expression in affected children. Some individuals require wheelchair assistance because of severe muscle weakness. Much more commonly, patients remain ambulatory, often assisted by leg braces or corrective foot surgery at the end of the second decade or in the third decade. The condition is compatible with normal longevity.

Clinical Neurophysiology

Motor and sensory conduction velocity is within the “demyelinating” range and thus is less than 60 percent of normal values in infants; in patients older than 3 years, it is less than 38 m/sec in all peripheral nerves. Conduction velocity changes little with increasing age, but there is a progressive reduction in the amplitude of the evoked muscle action potential, indicating axonal loss [Roy et al., 1989].

Genetics

HMSN type I is dominantly inherited. In addition, autosomal-recessive [Gabreels-Festen et al., 1992; Harding and Thomas, 1980] and X-linked forms of a similar disorder exist [Hahn et al., 1990; Rozear et al., 1987]. Autosomal-recessive demyelinating forms, which are now designated CMT type 4, tend to have an earlier onset and a higher incidence of ataxia, complete areflexia, and kyphoscoliosis than dominant types. Several recessive varieties have been cloned or linked to specific chromosomal regions, e.g., in inbred Tunisian (chromosome 8q13–21) [Ben Othmane et al., 1993a], Bulgarian (chromosome 8q24) [Kalaydjieva et al., 1996], and Algerian (chromosome 5q23–33) [Kessali et al., 1997] families. The genes for these conditions are listed in Table 89-2. Another form with florid myelin sheath changes, known as hereditary motor and sensory neuropathy with focally folded myelin or congenital dysmyelinating neuropathy, has been linked to chromosome 11q23. Even this latter condition, however, is heterogeneous. CMT type 4B1 is due to mutations of the myotubularin gene; CMT type 4B2, which is characteristically associated with glaucoma, is due to a mutation of the SBF2 gene; and CMT type 4B3 (also known as CMTIVH) is caused by FGD4 mutations. Similar histopathological changes are sometimes seen with MPZ mutations.

Hereditary Motor and Sensory Neuropathy Type II

Hereditary motor and sensory neuropathy (Charcot–Marie–Tooth disease) type II (CMT2) is heterogeneous and is usually dominantly inherited. Autosomal-recessive and X-linked forms of the disorder are known and will be discussed further [Hahn et al., 1990; Harding and Thomas, 1980; Rozear et al., 1987]. In fact, CMT2 has now been linked to at least 13 loci and 10 genes (see Table 89-2). Whilst CMT2A was initially linked to a missense mutation in the kinesin family member 1B-ss (KIF1B) gene in one pedigree, no such mutations have been identified in other affected kindreds. Mutations in the gene encoding a mitochondrial fusion protein, mitofusin 2 (MFN2), are now thought to be responsible for about 25 percent of CMT2A cases [Zuchner et al., 2004; Verhoeven et al., 2006]) (see below).

CMT2B is caused by missense mutations in RAB 7, which encodes the small guanosine triphosphatase late endosomal protein, which may have a role in axonal transport [Houlden et al., 2004]. It may be confused with hereditary sensory and autonomic neuropathy type I because of the presence of moderate sensory loss, with complicating ulcers in up to 50 percent of cases [Verhoeven et al., 2003]. Other subtypes of autosomal-dominant CMT2 are listed in Table 89-2.

In general, onset of clinical manifestations tends to be later in dominantly inherited HMSN type II than in type I. Muscle atrophy and weakness are milder and more prominent than sensory deficits, compared with the type I disorder. Otherwise, the clinical course of type II disease is similar to that found in type I.

The pathology is marked by axonal degeneration. Nerve hypertrophy and palpable nerve enlargement are not present. The onion bulb formation typical of type I disease is rarely seen. In one variant, focally enlarged myelinated axons with aggregations of neurofilaments have been described [Goebel et al., 1986]. In addition to the focal accumulation of intra-axonal neurofilaments in the myelinated fibers, similar structures have been seen without axonal enlargement in the nonmyelinated axons. Similar structures have been noted in fibroblasts and endothelial cells in muscle and skin. Whether these intra-axonal filaments describe a different disease process is unknown. Nerve conduction velocities are low-normal to slightly reduced.

A rather severe form of HMSN type II was designated hereditary motor and sensory neuropathy of neuronal type with onset in early childhood (EOHMSNA). Two large series of such patients were reported by [Ouvrier et al., 1981] and by [Gabreels-Festen et al., 1991]. The disorder accounts for up to 5 percent of childhood chronic neuropathies. The features of the disorder include sporadic occurrence or evidence of autosomal-recessive or, less commonly, dominant inheritance. In addition, onset of weakness within the first 5 years of life, rapid progression of weakness to almost complete paralysis below the elbows and knees by the second decade, moderate sensory changes in most cases, clinical electrophysiologic studies consistent with an axonal degenerative polyneuropathy, and histologic studies indicating neuronal (axonal) atrophy and degeneration of peripheral motor and sensory neurons are noted. CSF is usually normal. The condition advances rather rapidly, so that most patients are nonambulatory by the mid- to late teens. Approximately 50 percent of such Australian cases studied have been shown to be due to autosomal-dominant (CMT 2A) or recessive (compound heterozygous or homozygous) mutations of the mitofusin (MFN2) gene. Mitofusin2, a large transmembrane protein, promotes membrane fusion and is involved in the maintenance of the morphology of axonal mitochondria. Families with MFN2 mutations have been reported in which some members had variable upper motor neuron signs or optic atrophy in addition to peripheral neuropathy. MFN2 mutations thus have also been implicated in the causation of CMT disease associated with pyramidal tract features (HMSN type V) and with cases of CMT disease complicated by optic atrophy (HMSN type VI). A similar EOHMSNA phenotype due to mutations of the ganglioside-derived differentiation-associated protein 1 (GDAP1) gene has been seen, mainly in North African and Mediterranean countries.

Congenital and Early Infantile Axonal Types

Some infants are born with arthrogryposis secondary to an axonal neuropathy. This condition is often a nonprogressive disorder, presumably secondary to an intrauterine insult. It is not clear whether these disorders are hereditary. Other cases have been described in which infants a few weeks old have presented with talipes and, later, rapidly progressive respiratory distress, leading to death or permanent ventilatory support within the first year of life [Appleton et al., 1994; Vanasse and Michaud, 1992]. In some of these cases, clinical electrophysiologic and histopathologic examinations have been consistent with a form of spinal muscular atrophy affecting the diaphragm and distal muscles preferentially (SMARD) [Grohmann et al., 2003]. In others, investigations have confirmed the presence of an axonal neuropathy [Wilmshurst et al., 2000]. Mutations of the gene encoding the immunoglobulin mu binding protein (IGHMBP2) cause both of these disorders.

Hereditary Motor and Sensory Neuropathy Type III (Dejerine–Sottas Disease) and Hypomyelinating Neuropathies

Hypomyelinating neuropathies are disorders in which Schwann cells are, to a variable extent, incapable of forming normal myelin. Histopathologically, they are characterized by the presence of thin myelin sheaths, often with few or poorly compacted myelin lamellae, and by the presence of onion bulbs, which are often large and made up of thin lamellae and basal lamina remnants.

The most extreme form of hypomyelinating neuropathy, in which the patient is severely affected at birth by a condition resembling congenital spinal muscular atrophy, is sometimes termed congenital amyelinating neuropathy [Charnas et al., 1988; Karch and Urich, 1975; Kasman et al., 1976; Palix and Coignet, 1978; Seitz et al., 1986]. In this group, arthrogryposis is common, presumably because of lack of limb movements in utero. Due to respiratory problems and swallowing difficulties, these infants usually die when very young. Nerve conduction velocity is either unrecordable or extremely low. Peripheral nerve histopathologic examination reveals no (amyelination) or very little myelin and virtually absent onion bulbs. Such cases probably represent examples of the extreme end of the spectrum of clinical and pathologic severity resulting from myelin protein mutations. Cases of central and peripheral hypomyelination in association with juvenile-onset cataracts were due to mutations of DRCTNNB1A, which encodes hyccin, a membrane protein [Ugur and Tolin, 2008]. SOX10 mutations can also cause central and peripheral hypomyelination in combination with Waardenburg’s syndrome or with Hirschsprung’s disease. Less extreme but severe infantile hypomyelinating cases merge into the Dejerine–Sottas syndrome (HMSN type III). In the majority of cases, hypotonia and delay in walking to beyond the second year are observed, but most HMSN type III toddlers eventually do walk, although coordination is never fully normal. Ataxia is present in all patients and is probably due to a proprioceptive deficit. Distal weakness, more marked in the lower limbs, is present early. Proximal weakness and deformity of the hands and feet are not common in early childhood. Both become increasingly more obvious with advancing age, so that by the second decade proximal weakness is the rule. Deep tendon reflexes are usually absent. Clinical enlargement of nerves, with the median and other peripheral nerves feeling thicker than a pencil, is present in most HMSN type III patients by the end of the first decade or earlier. By the time adequate testing can be performed, moderate to severe sensory loss is present in most patients. By comparison, such marked sensory loss is rarely seen in CMT type I. Scoliosis often occurs early and tends to progress. Nerve conduction velocities are typically lower than 10 m/sec, probably because of loss of saltatory conduction. Prognosis is variable [Guzzetta et al., 1982]. Some patients clearly deteriorate over the first two decades [Tyson et al., 1997], but most patients we have been able to follow have shown little change over many years, except for the progression of limb deformities and scoliosis [Ouvrier et al., 1987].

Many, perhaps the majority of, cases of congenital hypomyelinating neuropathy and Dejerine–Sottas syndrome are the result of myelin protein mutations. Both (dominant) heterozygous PMP22 and myelin P0, as well as homozygous myelin P0 mutations, have been reported to cause the Dejerine–Sottas phenotype [Tyson et al., 1997; Valentijn et al., 1995; Warner et al., 1996]. In addition, homozygous inheritance of the chromosome 17p11.2–12 duplication (in which the patient has four copies of the PMP22 gene), compound heterozygous states involving a deletion and a point mutation of the PMP22 gene [Gonnaud et al., 1997], and a case of apparent homozygosity for HMSN type II [Sghirlanzoni et al., 1992], caused by a myelin P0 mutation [Taroni et al., 1996], have all been associated with the Dejerine–Sottas phenotype. Periaxin, EGR2, and FIG4 gene mutations are also rarely causative. The complexity of the genetics of the Dejerine–Sottas syndrome makes it important to study such cases and their families, wherever possible, by detailed molecular genetic analysis before genetic counseling is given. In addition to the preceding studies, two remarkable cases of recovery from a congenital hypomyelinating neuropathy were reported by [Ghamdi et al., 1997] and [Levy et al., 1997].

Hereditary Motor and Sensory Neuropathy Types IV to VII

The term hereditary motor and sensory neuropathy type IV was applied by Dyck to Refsum’s disease, but is not widely used. Dyck designated patients with spastic paraplegia, who had abnormalities in quantitative testing of sensation, sensory nerve conduction, and histometric evaluation of sural nerve, as well as a pattern of autosomal-dominant inheritance, as having HMSN type [Harding and Thomas 1984] reported 25 cases of peroneal muscular atrophy with pyramidal features. In contrast to [Dyck et al., 1975], these authors believed that peroneal muscular atrophy with pyramidal features is a separate disorder from hereditary spastic paraplegia but that it also demonstrates heterogeneity. The combination of hereditary motor and sensory neuropathy with optic atrophy was designated hereditary motor and sensory neuropathy type VI by [Dyck et al., 1975]. First described by Vizioli, this rare condition may be transmitted by autosomal-dominant or recessive inheritance [Ippel et al., 1995]. The combination of a neuropathy with familial retinitis pigmentosa, first reported by [Massion-Verniory et al., 1946] from Belgium, was designated HMSN type VII by [Dyck et al., 1975]. In the original family, a 34-year-old man rather abruptly developed visual and gait difficulties that worsened over the next 9 years. Two of his sisters had pigmentary retinopathy without evidence of neuropathy. CSF protein was elevated. A nerve biopsy was unhelpful. Cases of this combination are rare and, to the authors’ knowledge, have not been reported in childhood.

X-Linked Forms

Intermediate Forms of Charcot–Marie–Tooth Disease

Intermediate forms of CMT exist in which neurophysiological results fall between the axonal and demyelinating range (between 30 and 40 m/s in patients over 3 years of age). Nerve biopsy results tend to reflect this overlap. Such disorders may be caused by mutations of the dynamin 2, YARS, or even the MPZ gene, but are uncommonly recognized in childhood.

Distal Hereditary Motor Neuropathies

Traditionally, the distal hereditary neuropathies (dHMN) have been grouped with the spinal muscular atrophies. They are defined clinically by the presence of predominantly distal weakness with absent sensory changes. Motor nerve conduction velocities are normal or only mildly slow. Sensory conduction is normal. Sural nerve biopsies are also normal, but electromyography and biopsy studies of distal muscles show evidence of denervation. With the advances of molecular biology [Irobi et al., 2006], it has become clear that there is sometimes overlap, with sensory as well as motor neuron involvement, both clinically evident and apparent on laboratory investigation. A good example of this overlap is seen in the disorders caused by mutations of the gene encoding the immunoglobulin mu binding protein (IGHMBP2), in which respiratory failure in infancy is accompanied by either a severe sensorimotor polyneuropathy (SIANR) or, more commonly, spinal muscular atrophy (SMARD or dHMNVI). The types of dHMN are listed in Table 89-2.

Type I

Hereditary sensory and autonomic neuropathy type I is a dominantly inherited disorder, usually beginning in the second or third decade of life [Dyck, 1984]. The condition is mapped to 9q22.1–22.3 [Nicholson et al., 1996]. The disorder is caused by mutations of the SPTLC1 gene encoding serine palmitoyl transferase [Dawkins et al., 2001]. In some instances, genetic analysis has shown that a similar disease may be inherited as an autosomal-recessive condition rather than as the typical dominantly inherited condition with variable expression [Kondo et al., 1974]. Characteristically, the patient experiences lightning-like pains and develops perforating ulcers of the feet.

Cutaneous sensation and tendon reflexes are lost in the lower extremities [Berginer et al., 1984]. Pes cavus, hammer toes, and peroneal muscular weakness develop. Variability of disease expression is so great that some affected relatives may be asymptomatic, but 100 percent penetrance is evident by the age of 30 years, as reported in a large kindred by [Nicholson et al., 1996]. Spontaneous amputations of the distal limbs have occurred. Pathologic studies from such individuals have demonstrated nerve degeneration and bone necrosis [Teot et al., 1985]. As individuals advance into adulthood, the loss of all peripheral sensory modalities, except those of the face, has been reported [Nance and Kirby, 1985]. Hereditary deafness is an associated feature [Fitzpatrick et al., 1976; Nicholson et al., 1996]. Increased immunoglobulin A levels were found in members of three unrelated families [Whitaker et al., 1974]. In a separate family, both immunoglobulin A and immunoglobulin G levels rose as the disease progressed [Iwabuchi et al., 1976]. Sural nerve biopsy reveals marked loss of myelinated nerve fibers, especially large myelinated fibers, and loss of unmyelinated nerve fibers [Danon and Carpenter, 1985]. Treatment is limited and is generally preventive. Protection of the feet from injury by wearing appropriate shoes and avoiding jumping and falling is important. Meticulous attention to proper toenail trimming and treatment of plantar ulcers are other important measures. If conservative efforts fail, amputation of affected extremities is necessary [Gwathmey and House, 1984].

Type II

Hereditary sensory and autonomic neuropathy type II occurs as a congenital sensory neuropathy that is recessively inherited [Ohta et al., 1973]. The disorder is due to mutations of the HSN2 gene [Lafreniere et al., 2004]. In addition to loss of pain and temperature sensation, affected children have great difficulty recognizing objects by touch. Recurrent infections are common in the digits, and fractures may occur. As the disease progresses, mutilation of fingers and toes occurs. Motor nerve conduction is normal but sensory action potentials are absent. Sural nerve biopsies reveal a marked decrease in myelinated fibers of all calibers, as well as of unmyelinated fibers. There are possibly several subtypes of this disorder, one of which is thought to be nonprogressive [Ferrière et al., 1992].

Type III

Hereditary sensory and autonomic neuropathy type III is otherwise known as familial dysautonomia or the Riley–Day syndrome (see Chapter 98).

Type IV

Hereditary sensory and autonomic neuropathy type IV is a congenital recessively inherited sensory neuropathy, usually associated with mental retardation [Dyck, 1984]. Anhidrosis is a feature of the condition [Gillespie and Perucca, 1960; Pinsky and DiGeorge, 1966; Swanson, 1963; Vassalla et al., 1968]. [Rosemberg et al., 1994