Journal of the Peripheral Nervous System 17:32–52 (2012) REVIEW Demyelinating prenatal and infantile developmental neuropathies Eppie M. Yiu1,2 and Monique M. Ryan1,2,3 1Children’s Neuroscience Centre, Royal Children’s Hospital; 2Murdoch Childrens Research Institute, Flemington Rd, Parkville, 3052, Victoria, Australia; and 3Department of Paediatrics, The University of Melbourne, Australia Abstract The prenatal and infantile neuropathies are an uncommon and complex group of conditions, most of which are genetic. Despite advances in diagnostic techniques, approximately half of children presenting in infancy remain without a specific diagnosis. This review focuses on inherited demyelinating neuropathies presenting in the first year of life. We clarify the nomenclature used in these disorders, review the clinical features of demyelinating forms of Charcot-Marie-Tooth disease with early onset, and discuss the demyelinating infantile neuropathies associated with central nervous system involvement. Useful clinical, neurophysiologic, and neuropathologic features in the diagnostic work-up of these conditions are also presented. Key words: Charcot-Marie-Tooth disease, Dej´ erine–Sottas´ disease, demyelination, paediatric, peripheral neuropathy Introduction Aetiology The prenatal and infantile neuropathies are an In a large cohort of 260 children with biopsy- uncommon and complex group of conditions with confirmed peripheral neuropathy, 50 (19.2%) were broad phenotypic and genotypic diversity. Most symptomatic in infancy, of whom 48% had a infantile neuropathies have a genetic basis. This review demyelinating and 42% an axonal disorder (Wilmshurst focuses on inherited demyelinating neuropathies et al., 2003). Whilst many of these cases presented presenting in the first year of life. Axonal neuropathies prior to the era of genetic diagnosis, 20 children presenting during this period will be reviewed fell under the rubric of Charcot-Marie-Tooth disease separately. Whilst progress has been made in the (CMT), 19 of whom had a demyelinating form of diagnosis of prenatal and infantile neuropathies, at CMT. Children with a demyelinating phenotype were this point more than half of children presenting in the more likely to receive a definitive diagnosis (six had first year of life remain without a specific diagnosis. heterozygous point mutations in PMP22 or MPZ). With advances in molecular genetic techniques, More recently, in a series of 77 children with infantile the already rapidly expanding number of genes neuropathies (58% demyelinating, 20% axonal, and attributed to infantile neuropathies is set to further 22% undefined), 35 children (45%) received a increase. diagnosis involving mutations in 1 of 11 genes, most of which were associated with demyelinating forms of CMT (Baets et al., 2011). This emphasises the genetic Address correspondence to: Monique Ryan, Associate Professor, heterogeneity of the infantile neuropathies, but also Children’s Neuroscience Centre, Royal Children’s Hospital, Flemington Rd, Parkville, 3052 Victoria, Australia. Tel: (+61)3-9345 the fact that over half of children remain without a 5661; Fax: (+61)3-9345 5977; E-mail: [email protected] definitive diagnosis. © 2012 Peripheral Nerve Society 32 Yiu and Ryan Journal of the Peripheral Nervous System 17:32–52 (2012) Clinical Presentation well as detecting and managing complications of the neuropathy. Most infants with early onset neuropathies tend to display one of two phenotypes. The first group has clear prenatal/neonatal onset and presents at birth with hypotonia, arthrogryposis, and respiratory Diagnostic Process insufficiency. The second (and more common) group To aid diagnosis, it is important to determine: presents later in infancy with delayed motor devel- (1) whether the infant has an isolated peripheral opment and/or foot deformities, after an uneventful neuropathy or neuropathy in association with a neonatal period (Baets et al., 2011). central nervous system (CNS) disorder; (2) whether the In the first group a history of decreased foetal neuropathy is primarily demyelinating/hypomyelinating movements, intra-uterine growth retardation and or axonal; (3) the inheritance pattern; and (4) if polyhydramnios may be obtained, and delivery of a there are any distinguishing features on clinical, hypotonic infant may result in obstetric complications neurophysiologic, or neuropathologic examination. such as obstructed labour and birth asphyxia, masking Nerve conduction studies provide vital information the underlying peripheral neuropathy. Ventilatory in determining if a neuropathy is primarily demyelinat- support is often required and early mortality ing or axonal. It is important to remember that con- common. duction velocities increase during the first 2–3 years In contrast to adults, in whom distal weakness of life. Normative values for age should always be ref- and sensory loss are the predominant features of a erenced (Miller and Kuntz, 1986; Parano et al., 1993). neuropathy, infants in the second group usually have Nerve conduction studies, particularly sensory studies, delayed motor milestones (an indicator of infantile can be technically difficult in infants and neonates, so onset) and areflexia. Proximal weakness, foot defor- absent sensory responses should be interpreted with mity, scoliosis, and congenital hip dysplasia may be caution. Infants with severe neuropathies may have apparent, and the clinical features may mimic myopa- unobtainable motor and sensory responses, making it thy. Facial weakness and tongue fasciculations may difficult to discriminate between a primarily demyeli- be present, reflecting a severe neuropathic process. nating or axonal process. Testing of more proximal Nerve hypertrophy is visible or palpable in some hyper- nerves (such as the phrenic nerve) can be helpful in trophic neuropathies, but is difficult to assess and not this instance, while needle electromyography (EMG) always present. Some distinguishing clinical features helps to distinguish myopathies from neuropathies. In of infantile demyelinating neuropathies are presented addition, conduction slowing may be so severe that in Table 1. Features of axonal infantile neuropathies the time base for nerve conduction testing needs to will be reviewed separately. be adjusted to identify very delayed responses. Once a neuropathy is diagnosed, the assessment Nerve biopsy can be very informative in determin- should focus on identifying a specific diagnosis, as ing the basis of prenatal and infantile neuropathies. Table 1. Clinical clues to the diagnosis of infantile demyelinating neuropathies. Clinical feature Clinical phenotype Gene Pupillary abnormalities CHN, DSD, CMT1B MPZ CMT4C SH3TC2 Multiple cranial neuropathies CHN, DSD, CMT4E EGR2 Prominent foot and hand deformities CMT4A, CMT2H/K GDAP1 CMT4C SH3TC2 Severe spinal deformities CMT4C SH3TC2 Asymmetric weakness DSD, CMT4J FIG4 Post-traumatic rapid progression of weakness DSD, CMT4J FIG4 Vocal cord paresis CMT4A, CMT2H/K GDAP1 CMT4B1 MTMR2 Diaphragmatic involvement CMT4A, CMT2H/K GDAP1 Glaucoma CMT4B2 MTMR13 Prominent sensory involvement DSD, CMT4F PRX Congenital cataracts HCC DRCTNNBIA CCFDN CTDP1 Raised creatine kinase Merosin-deficient CMD LAMA2 CCFDN, congenital cataracts facial dysmorphism neuropathy syndrome; CHN, congenital hypomyelinating neuropathy; CMD, congenital muscular dystrophy; CMT, Charcot-Marie-Tooth disease; DSD, Dej´ erine–Sottas´ disease; HCC, hypomyelination and congenital cataract. 33 Yiu and Ryan Journal of the Peripheral Nervous System 17:32–52 (2012) Table 2. Neuropathologic clues in the diagnosis of and some are associated with sensorineural hearing infantile demyelinating neuropathies. loss. Neuropathologic feature Clinical/genetic phenotypes The long-term prognosis of individuals with early onset demyelinating neuropathies is variable and not Focal myelin folding Frequently present well documented. Outcomes are dependent not only MPZ-related CHN/DSD on the underlying genetic mutation, but likely also CMT4B1 (MTMR2) environmental and epigenetic factors given the inter- CMT4B2 (MTMR13) and intra-familial variability often present. Individuals CMT4F (PRX) CMT4H (FGD4) with significant respiratory involvement tend to have Occasionally present a poorer prognosis than those without respiratory EGR2-related neuropathies compromise. GDAP1-related neuropathies Appropriate genetic counselling should always be CMT4C (SH3TC2) Uncompacted myelin MPZ-related CHN/DSD provided to families. Long Schwann cell CMT4C (SH3TC2) cytoplasmic processes Node of Ranvier CMT4C (SH3TC2) disorganisation Demyelinating Forms of CMT with Early Paranodal abnormalities CMT4F (PRX) Onset CMTX1 (Cx32) Terminology CHN, congenital hypomyelinating neuropathy; CMT, Charcot- Marie-Tooth disease; DSD, Dej´ erine–Sottas´ disease. Congenital hypomyelinating neuropathy (CHN), Dej´ erine–Sottas´ disease (DSD, also referred to as Specific neuropathologic abnormalities may point to CMT3 or hereditary motor and sensory neuropathy particular genetic syndromes; distinguishing nerve (HMSN) III) and CMT4 (also referred to as autosomal biopsy features of demyelinating neuropathies are recessive CMT1, ARCMT1) are all forms of demyeli- presented in Table 2. Acquired and potentially treat- nating CMT with early onset. The nomenclature is able causes of neuropathies such as infantile CIDP very confusing, as the original descriptions and classi- (although rare), may mimic or occur superimposed on fication were made prior to the availability of genetic genetic neuropathies,