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].

Only gold members can continue reading. Log In or Register to continue

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