Abbreviations: DPN, diabetic peripheral neuropathy; EMG, electromyogram; GBS, Guillain-Barré syndrome; HMSN, hereditary motor and sensory neuropathy; HNPP, hereditary neuropathy with liability to pressure palsy; HSAN, hereditary sensory autonomic neuropathy; QST, quantitative sensory testing.

Peripheral polyneuropathies presenting in children may be hereditary in nature due to genetic mutations in one or more peripheral nerve proteins. When expressed in the infant or early neonatal period, these may be part of a developmental syndrome and the congenital neuropathy may be one of many abnormalities present in that patient. In other cases, the peripheral neuropathy is expressed as the presenting symptom in later childhood with weakness, sensory loss, frequent falls, pain, or recurrent palsies. These later forms of peripheral neuropathy are discussed here.

Hereditary Motor and Sensory Neuropathies

The second most common form of CMT is X-linked Charcot-Marie-Tooth (CMTX) and is responsible for approximately 10% of all CMT cases. It is associated with mutations in the gap junction protein beta 1 gene (GJB1 encoding for connexin-32.2 protein). Current research is aimed at evaluating the benefit of neurotrophic factors in CMT disorders on the progression of disease (3).

Hereditary Sensory and Autonomic Neuropathies

Hereditary sensory and autonomic neuropathies (HSANs) are of five subtypes, all characterized by impairment in sensation due to loss of unmyelinated and small myelinated peripheral nerve fibers. Autonomic involvement can be seen as well. Electrophysiologic testing can reveal significant symmetric amplitude loss in sensory nerves distally (sural), and when severe, there is loss of sensory nerve responses but nerve conduction velocities may be normal. Motor conductions are typically normal. Subtype IV is associated with pain insensitivity. This condition can be associated with injuries due to loss of sensation to pain, oral mutilation, fractures, and anhidrosis. This condition can be very functionally debilitating, and delay in diagnosis can cause severe morbidity (4). The intradermal histamine test demonstrates lack of a normal axon flare response and is consistent with a diagnosis of HSAN. Since large myelinated fibers are generally not impacted significantly, electrophysiology testing may be normal or reveal mild reductions in sensory amplitude and mild prolongation of distal latencies. Quantitative sensory testing will be markedly abnormal for temperature thresholds.

Spinal Muscular Atrophies

The most common forms are autosomal recessive and are due to homozygous deletion of exon 7 in the SMN1 gene. The SMN gene produces an SMN protein involved in mRNA synthesis affecting motor neurons of the spine and peripheral nervous system. The severity of the disorder depends on the extent of involvement of other exons on the SMN1 gene and the number of copies of SMN2 present. If more than two copies of SMN2 are present, it mitigates the severity of the disorder. Involvement in infancy (SMA1) is usually the most severe form of the disease with respiratory compromise and early death. SMA2 typically has onset after 6 months of age and severity is variable, with some patients continuing into adulthood. The mildest form is SMA3 with onset in adolescence typically with motor weakness and slower overall progression of disease. Electrophysiological findings in these forms include motor axon loss without significant conduction slowing or latency changes and generally sparing of sensory nerves. The presence electrophysiologically of fasciculations and the presence of findings in several myotomes help to support the diagnosis.

Mitochondrial Deficiency Neuropathies

Lysosomal and Glycogen Storage Disorders

Although classically described as a muscle disorder, Pompe’s disease is a glycogen storage disease type II disorder also known as acid maltase deficiency (5). It is called acid maltase deficiency because it encompasses mutations in the gene encoding the lysosomal enzyme acid alpha glucosidase or GAA and is inherited in an autosomal recessive pattern. As a result of this mutation, an abnormal accumulation of glycogen of normal structure occurs within the lysosomes of various organs and in particular in skeletal, hepatic, and cardiac muscle in infants. The storage of glycogen occurs also in the central and peripheral nervous systems. Electrophysiologic findings typically involve motor nerves with amplitude loss, while sensory nerves do not typically show abnormal findings. Muscle fiber irritability is seen on needle EMG, particularly in proximal muscles (6).

Giant Axonal Neuropathy

Giant axonal neuropathy (GAN) is a rare pediatric neurodegenerative disease characterized by “giant” axons pathologically. These giant axons are caused by accumulations of intermediate filaments. GAN is associated with severe and chronic progression. Onset of disease clinically is by age 3 years, with progressive systemic involvement and respiratory compromise typically by the third decade. Central nervous system (CNS) involvement includes ataxia, oculomotor apraxia, and dysmetria. Patients may also have dysarthria and hearing loss (7). This disorder is an autosomal recessive disease with mutations in the GAN gene, which encodes for a protein called gigaxonin, involved in cytoskeleton support. Nerve conduction testing reveals significantly reduced motor amplitudes with mild-to-normal conduction velocities and absent sensory responses.

Sickle Cell Disease

Sickle cell disease is an autosomal recessive disorder in which pain is known to occur during crisis. However, reports of neuropathic pain symptoms are described in approximately 40% of sickle cell patients, independent of sickle cell crisis. Symptoms increase in intensity with longer disease duration. The pain is described as thermal hyperalgesia and can be seen in adolescent patients along with abnormalities on quantitative sensory testing. Electrophysiology reveals the presence of a small fiber neuropathy (8).

ACQUIRED PERIPHERAL NEUROPATHIES

Guillain-Barré Syndrome

Nutritional and Malabsorption Syndromes

Nutritional and vitamin deficiencies including B12, folate, and thiamine can be associated with a peripheral neuropathy, often axonal in nature. These deficiencies may happen due to gastrointestinal diseases such as Crohn’s, malnutrition, or alcohol use. In adolescents, these vitamin deficiencies can be seen with anorexia nervosa, an eating disorder characterized by starvation, vomiting, and severe weight loss (10). Vitamin E deficiency can be associated with a distal motor neuropathy and mutation in the alpha-tocopherol transfer protein gene. Electrophysiologic findings include neurogenic motor units and low-amplitude to absent motor responses on nerve conduction testing (11). Vitamin E deficiency and peripheral neuropathy have also been shown to occur in patients with cystic fibrosis. Cystic fibrosis is an autosomal recessive multisystem disorder affecting 1/3,200 live births. The peripheral neuropathy is responsive to vitamin E supplementation.

Chemotherapy-Induced Peripheral Neuropathy

With improvements in pediatric cancer, chemotherapeutic agents have been more widely used in pediatric patients. These patients report the development of neuropathic symptoms. An example is that of vincristine-induced neuropathy in the treatment of acute lymphoblastic leukemia (ALL). ALL is the most common pediatric cancer responsible for 30% of all cases under the age of 14 years. Clinically, patients typically present 2+ years after chemotherapy and may have paresthetic complaints and loss of ankle reflexes on clinical exam (12). Electrophysiologic findings include predominately motor amplitude loss.

As in adults, the most common form of peripheral neuropathy due to diabetes in children is a distal symmetric sensory-motor form. Most pediatric patients with diabetic peripheral neuropathy (DPN) are asymptomatic but have subclinical disease based on clinical examination and electrophysiology studies. There is increased risk with type 1 diabetes more than 5 years or with post-pubertal type 2 diabetics. Nerve conduction testing reveals slowing of nerve conduction velocities involving motor and sensory nerves along with latency prolongations, and severe amplitude loss can be seen as well (13).

Peripheral neuropathies in pediatric patients have a variety of clinical and electrophysiologic presentations. In some cases, these presentations are similar to those found in adults. In other cases, the pediatric presentation is unique. Determining whether the underlying process is inherited or acquired can be done based on clinical and family history. Electrophysiology can support the clinical diagnosis and help guide the determination of etiologic factors. In some cases, EMG can be used to monitor treatment outcomes or progression of disease.

REFERENCES

   1.  Kachko L, Ami S, Lieberman A, et al. Neuropathic pain other than CRPS in children and adolescents: incidence, referral, clinical characteristics, management, and clinical outcomes. Pediatr Anesth. 2014;24(6):608–613.

   2.  Ramchandren S, Jaiswal M, Feldman, E. Effect of pain in pediatric inherited neuropathies. Neurology. 2014;82:793–797.

   3.  Sahenk Z, Galloway G, Clark K, et al. AAV1.NT-3 Gene Therapy for Charcot–Marie–Tooth Neuropathy. Mol Ther. 2014;22(3):511–521.

   4.  van den Bosch GE, Baartmans MG, Vos P, et al. Pain insensitivity syndrome misinterpreted as inflicted burns. Pediatrics. 2014;133(5):e1381–e1387.

   5.  Burrow TA, Bailey LA, Kinnett D, et al. Acute progression of neuromuscular findings in infantile Pompe disease. Pediatr Neurol. 2010;42(6):455–458.

   6.  Landrieu P, Baet J, De Jonghe P. Hereditary motor-sensory, motor and sensory neuropathies in childhood. In: Dulac O, Lassonde M, Sarnat HB. eds. Handbook of Clinical Neurology. Pediatric Neurology Part III. Vol 113 (3rd series). Amsterdam: Elsevier BV;2014.

   7.  Johnson-Kerner B, Roth L, Greene JP, et al. Giant axonal neuropathy: an updated perspective on its pathology and pathogenesis. Muscle Nerve. 2014;50:467–476.

   8.  Brandow A, Farley R, Panepinto J. Neuropathic pain in patients with sickle cell disease. Pediatr Blood Cancer. 2014;61:512–517.

   9.  Ryan, Monique M. Pediatric Guillain-Barré syndrome. Curr Opin Pediatr. 2013;25(6):689–693.

10.   Renthal W, Marin-Valencia I, Evans P. Thiamine deficiency secondary to anorexia nervosa: an uncommon cause of peripheral neuropathy and Wernicke encephalopathy in adolescence. Pediatr Neurol. 2014;51(1):100–103.

11.   Fusco C, Frattini D, Pisani F, et al. Isolated vitamin E deficiency mimicking distal hereditary motor neuropathy in a 13-year-old boy. J Child Neurol. 2008;23(11):1328–1330.

12.   Jain P, Gulati S, Seth R. Vincristine-induced Neuropathy in Childhood ALL (Acute Lymphoblastic Leukemia) Survivors: Prevalence and Electrophysiological Characteristics. J Child Neurol. 2014;29(7):932–937.

13.   Mah JK, Pacaud D. Diabetic neuropathy in children. In Zochodne DW, Malik RA, Eds. Diabetes and the Nervous System. Handbook of Clinical Neurology. Vol. 126 (3rd series). Amsterdam: Elsevier BV;2014.