Acquired and Hereditary Neuropathies

1. Anatomical site(s) that are clinically involved:
 − Brain
 − Cranial nerve(s)
 − Spine
 − Nerve plexus
 − Sensory ganglia
 − Nerve root(s)
 − Motor neuron
 − Peripheral nerve(s)
2. Non-neurological findings
 − Non-neurological organ involvement
 − Concomitant diseases (auto-immune disease, cardiac disease)
 − Toxin/medication exposures
 − Family history, consanguinity
3. Age at symptom onset
4. Time course of neuropathy: acute, sub-acute or chronic
5. Pattern of peripheral nerve involvement
 − Polyneuropathy
 − Mononeuropathy
 − Mononeuritis multiplex
6. Peripheral nerve type(s) and fiber size(s) involved:
 − Motor
 − Sensory, large fiber (vibration, proprioception, two-point discrimination)
 − Sensory, small fiber (pain, temperature, light touch)
 − Autonomic
7. Neurophysiologic features
 − Axonal versus demyelinating
 − Uniform versus non-uniform

Anatomical Site(s) Involved

Children with suspected neuropathy will often show clinical findings in other areas of the central or peripheral nervous system. By identifying abnormalities elsewhere along the neuraxis, one can obtain important clues to narrow the differential diagnosis and direct investigations.
Proper localization mandates a detailed neurologic examination with characterisation of the pattern of weakness, the extent and location of sensory loss, changes in the deep tendon reflexes, and presence of cerebellar signs such as ataxia and dysdiadochokinesia.
Concomitant central nervous system involvement, including cognitive deficits or regression, seizures and/or psychiatric symptoms may point to systemic, genetic or metabolic causes of neuropathy [4, 5]. Several rare hereditary disorders of metabolism present during infancy or early childhood with peripheral nerve involvement and varying degrees of involvement of the central nervous system. These conditions include Krabbe disease, metachromatic leukodystrophy, peroxisomal disorders, Cockayne syndrome, giant axonal neuropathy, infantile neuroaxonal dystrophy and hereditary tyrosinemia. Central nervous system symptoms often overshadow the concomitant peripheral neuropathy in these conditions, but identification and characterization of the neuropathy can be helpful in narrowing the differential diagnosis. MRI of the brain is indicated in such cases, with additional metabolic testing to investigate for leukodystrophies, mitochondrial disorders (e.g., POLG mutations), peroxisomal disorders, Brown-Vialetto-Van Laere (BVVL) syndrome and/or toxin exposure.
Pertinent family history can provide further insight, including information pertaining to inheritance patterns. In some cases a focused examination of family members can be helpful in children with suspected neuropathies.
When cranial neuropathies are the first or dominant manifestation of a peripheral neuropathy, the differential diagnosis may often be narrowed accordingly. Diphtheria remains an important world-wide cause of acquired neuropathy with outbreaks reported [6]. Patients initially present with pharyngitis that is often associated with a grayish-white pseudomembrane in the throat. About 15% of patients develop neurological complications with the first neurological symptoms being bulbar dysfunction caused by diphtheria toxin-mediated cranial nerve paralysis. Almost all patients who develop a demyelinating polyneuropathy will have preceding cranial nerve involvement, making this an important diagnostic clue [6]. Other infectious causes including Lyme disease, which often presents with a unilateral facial nerve palsy and less commonly with other cranial nerve involvement [7, 8]. Children with the Miller-Fisher variant of Guillain-Barré syndrome will present with a triad of ophthalmoplegia, ataxia and areflexia [9]. It is important to note that cranial neuropathies may be present in traditional cases of Guillain-Barré syndrome; it is only when the cranial nerves constitute the predominant region of peripheral nerve involvement that Miller-Fisher syndrome should be considered.
Spinal cord involvement is differentiated from peripheral neuropathies by the well demarcated sensory level and presence of sphincter (bowel, bladder) dysfunction. Peripheral neuropathies by contrast show a degree of nerve injury that is proportion to axon length, where longer axons show more severe changes relatively earlier in the disease course. As a result, weakness and sensory loss resulting from peripheral neuropathy are initially seen in the distal lower extremities, though patchy radicular involvement may occur in the setting of inflammatory neuropathies, giving rise to a mixed distal/myotomal pattern in some patients. Deep tendon reflexes are typically depressed or absent in peripheral neuropathies, while the plantar responses remain flexor. Extensor plantar responses in the setting of depressed or absent deep tendon reflexes reflect spinal or cerebral involvement, as seen in Friedreich ataxia and metachromatic leukodystrophy.

Non-neurological Findings

Non-neurological symptoms and signs can provide the clinician with important clues to the diagnosis of many peripheral neuropathies. Involvement of organs such as the liver, spleen, heart, skin and lymphatic tissues increases the likelihood of specific underlying diseases in children with polyneuropathy. The general physical examination should include the skin, abdomen and cardiorespiratory systems, looking for clues suggestive of storage disorders or other inborn errors of metabolism. Non-neurological symptoms and signs suggestive of the aetiology of pediatric neuropathies are summarised in Table 18.2.
Table 18.2
Non-neurological findings suggestive of causation of pediatric neuropathies
Sign/symptom
   
Ocular
Optic atrophy
Mitochondrial disease (Friedreich ataxia, OPA1), CMT2A, CMT4A
 
Retinis pigmentosa
Peroxisomal diseases, mitochondrial disorders, ataxia with vitamin E deficiency
 
Ophthalmoplegia
Mitochondrial disorders, Miller Fisher syndrome
Ear
Hearing loss
Brown-Vialetto-van Laere syndrome, CMT1B, CMTX, Cockayne syndrome
Throat
Pharyngitis
Diphtheria
 
Discoloured, enlarged tonsils
Tangier disease
Skin
Hypopigmentation
Leprosy
 
Hyperpigmentation
Adrenoleukodystrophy (buccal), diabetes (acanthosis nigricans)
 
Angiokeratomas
Fabry disease
 
Purpura
Henoch-Schonein purpura
 
Discoid rashes
Systemic lupus erythematosus
 
Photosensitivity
Systemic lupus erythematosus, Cockayne syndrome, xeroderma pigmentosum
 
Desquamation
Arsenic poisoning
 
Nail changes (Mees’ lines)
Arsenic and thallium poisoning
Hair
Alopecia
Thallium poisoning
 
Curly, kinking hair
Giant axonal neuropathy
Cardiac
Cardiomyopathy
Mitochondrial disorders, Friedreich ataxia, ataxia with vitamin E deficiency
 
Conduction defects
Mitochondrial disorders, glue/solvent abuse
Respiratory
Diaphragmatic weakness
Spinal muscular atrophy with respiratory distress, Brown-Vialetto-van Laere syndrome
Gastro-intestinal
Abdominal pain
Mitochondrial disorders, Fabry disease, arsenic and lead poisoning
 
Pseudo-obstruction
Mitochondrial disorders
Systemic
Lymphadenopathy
Lymphoma
 
Hepatomegaly
Tyrosinemia, hemophagocytic syndromes
Extremities
Arthritis
Lyme disease, Farber disease
 
Xanthomas
Cerebrotendinous xanthomatosis
Cerebral
Cognitive regression
Leukodystrophies, mitochondrial syndromes, peroxisomal disorders, lead toxicity
 
Seizures
Merosin-deficient congenital muscular dystrophy
Autonomic symptoms—cardiac arrhythmias, hypotension or hypertension, abnormal sweating and trophic skin changes, bowel and bladder dysfunction—may be seen in specific acquired and genetic neuropathies. One classic example, described in Chap. 17, is the Horner syndrome seen in cases of traumatic nerve root avulsion at the neck/shoulder.

Age at Symptom Onset

Age of first symptom onset is a helpful clue to determining the underlying cause of childhood neuropathies (Table 18.3). Many hereditary or metabolic causes of polyneuropathy are symptomatic from birth, causing hypotonia, hypo- or areflexia, contractures of major joints (arthrogryposis multiplex congenita), feeding difficulties, and/or motor or global developmental delay. Early-onset peripheral neuropathies may be isolated (e.g., congenital hypomyelinating neuropathy, which is a severe form of Charcot-Marie-Tooth disease) or can be associated with combined peripheral and central nervous system findings (e.g., Krabbe disease, metachromatic leukodystrophy, giant axonal neuropathy, and mitochondrial diseases). The severity of the disease phenotype can also vary significantly, particularly with inborn errors of metabolism.
Table 18.3
Age and temporal pattern of symptom onset in pediatric neuropathies
 
Congenital and infancy
Childhood to adolescent onset
Acute onset
Guillain-Barré syndrome
Guillain-Barré syndrome
 
Mitochondrial disorders
Hereditary neuropathy with tendency to pressure palsies (HNPP)
 
Brown-Vialetto-van Laere syndrome
Mitochondrial neuropathies
   
Toxic neuropathies
   
Porphyria
   
Diphtheria neuropathy
   
Tyrosinemia
   
Tangier disease
   
Infectious neuropathies
Sub-acute or chronic
Early-onset forms of CMT (Congenital hypomyelinating neuropathy, Déjerine-Sottas disease)
Charcot-Marie-Tooth disease
 
Brown-Vialetto-van Laere syndrome
Chronic inflammatory demyelinating neuropathy
 
Mitochondrial neuropathies
Brown-Vialetto-van Laere syndrome
 
Neuropathies associated with lysosomal storage disorder (Krabbe, MLD)
Mitochondrial neuropathies
 
Neuropathies associated with other inborn errors of metabolism/genetic disorders—giant axonal neuropathy, Cockayne disease, merosin-deficient congenital muscular dystrophy, etc.
Friedreich ataxia
 
Hereditary sensory and autonomic neuropathies
Neuropathies associated with lysosomal storage disorder (Krabbe, MLD, Fabry disease)
   
Neuropathies associated with other inborn errors of metabolism/genetic disorders—giant axonal neuropathy, Cockayne disease, merosin-deficient congenital muscular dystrophy, etc.
   
Hereditary sensory and autonomic neuropathies
Historically, infants with congenital hypo- or demyelinating neuropathies were diagnosed as having Déjerine-Sottas disease or CMT type 3 (CMT3). With advances in molecular genetics it has become apparent that mutations in genes causative of CMT1 (autosomal dominant demyelinating CMT), CMT2 (autosomal dominant axonal CMT), and CMT4 (autosomal recessive CMT) (Table 18.4) are allelic with these severe congenital neuropathies, suggesting that these neuropathies lie in a spectrum of severity rather than in distinct phenotypic categories.
Table 18.4
Classification of Charcot-Marie-Tooth disease
CMT type 1: Autosomal dominant, demyelinating, 60% of all CMT
CMT1A
PMP22 duplication
70–80% of all CMT1
Pes cavus
CMT1B
MPZ mutation
5–10% of all CMT1
More severe weakness than CMT1A
CMT1C
LITAF mutation
1–2% of all CMT1
Early onset
CMT1D
EGR2 mutation
1–2% of all CMT1
 
CMT1E
PMP22 point mutation
<5% of all CMT1
 
CMT1F
NEFL mutation
<5% of all CMT1
 
HNPP
PMP22 deletion
<10% of all CMT1
Tendency to pressure palsies
CMT type 2: Autosomal dominant, axonal, 20% of all CMT cases
CMT2A1
KIF1B mutation
Rare
 
CMT2A2
MFN2 mutation
20–30% of CMT2
 
CMT2B
RAB7 mutation
Rare
 
CMT2B1
LMNA mutation
Rare
 
CMT2C
TRPV4 mutation
Rare
 
CMT2D
GARS mutation
Rare
 
CMT2E
NEFL mutation
Rare
 
CMT2F
HSPB1 mutation
Rare
 
CMT2G
Unknown
Rare
 
CMT2H/K
GDAP1 mutation
Rare
 
CMT2I/J
MPZ mutation
Rare
 
CMT2LCMT2M DNM2 RareCMT2N AARS RareCMT2O DYNC1H1 RareCMT2P LRSAM1 RareCMT2Q DHTKD1 RareCMT2R TRIM2 RareCMT2S IGHMBP2 RareCMT2T DNAJB2 RareCMT2U MARS RareCMT2V NAGLU RareCMT2W HARS Rare
HSPB8 mutation
Rare
 
CMT type X: X-linked, intermediate demyelinating/axonal
CMTX1
GJB1 (Cx32) mutation
90% of CMTX
 
CMTX2
 
<10% of CMTX
 
CMTX3
 
<10% of CMTX
 
CMTX5
PRPS1 mutation
<5% of CMTX
 
CMT type 4: Autosomal recessive, total 5–10% of all CMT cases
CMT4A
GDAP1 mutation
25% of all CMT4
 
CMT4B1
MTMR2 mutation
Rare
 
CMT4B2
SBF2 mutation
Rare
 
CMT4C
SH3TC2 mutation
Rare
 
CMT4D
NDRG1 mutation
Rare
 
CMT4E
EGR2 mutation
Rare
 
CMT4F
PRX mutation
Rare
 
CMT4H
FGD4 mutation
Rare
 
CMT4J
FIG4 mutation
Rare
 

Time Course of the Neuropathy (Acute, Sub-acute or Chronic)

Polyneuropathies can be subdivided according to how rapidly a patient’s symptoms progress (Table 18.3). Acute-onset neuropathies such as Guillain-Barré syndrome, vasculitic neuropathies, trauma, and some metabolic neuropathies (e.g., hereditary tyrosinemia and porphyria) can become symptomatic within days to weeks.
Guillain-Barré syndrome (GBS) is the most common form of acute flaccid paralysis in childhood [10]. GBS is an acute-onset, autoimmune disorder in which T lymphocytes invade peripheral nerves and Schwann cells, activating antibody and complement deposition within these structures [11]. GBS is subclassified, on the basis of its clinical and neurophysiological findings, as acute inflammatory demyelinating polyradiculoneuropathy (AIDP), Miller-Fisher syndrome (MFS), or acute motor axonal neuropathy (AMAN). AIDP is the most common subset of pediatric GBS in the Western world, while well-documented outbreaks of AMAN occur in some Asian countries. MFS occurs in children but is rare in that age group. Children with GBS present with rapidly evolving, symmetrical muscle weakness, often associated with pain or paraesthesias, and with diminished or absent muscle tendon reflexes. Symptoms typically develop over several days. Children may complain of limb pain or paraesthesias, and these may be the primary complaints in some cases. The degree of weakness varies. Respiratory failure and autonomic instability are common complications of pediatric GBS [10].
Metabolic causes of acute weakness include hereditary tyrosinemia and porphyria. Hereditary tyrosinemia is a rare autosomal recessive disease, usually presenting with liver disease and Fanconi syndrome, in which some children have acute neurological crises that may include an acute painful axonal polyneuropathy [12]. Acute intermittent porphyria (AIP) is the most common form of porphyria in childhood, presenting with acute episodes of neuropathy and/or paralysis and respiratory failure, sometimes after exposure to particular medications [13]. AIP may also have a GBS-like presentation in some patients [14].

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Nov 18, 2017 | Posted by in PEDIATRICS | Comments Off on Acquired and Hereditary Neuropathies

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