Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum

Claudie Gauvreau; Jean-Denis Brisson; Nicolas Dupré

Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum

Synonyms: Agenesis of Corpus Callosum with Peripheral Neuropathy (ACCPN), Andermann Syndrome

Gauvreau C, Brisson JD, Dupré N.

Publication Details

Estimated reading time: 20 minutes

Summary

Clinical characteristics.

Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC), a neurodevelopmental and neurodegenerative disorder, is characterized by severe progressive sensorimotor neuropathy with resulting hypotonia, areflexia, and amyotrophy, and by variable degrees of dysgenesis of the corpus callosum. Mild-to-severe intellectual disability and "psychotic episodes" during adolescence are observed. Sensory modalities are moderately to severely affected beginning in infancy. The average age of onset of walking is 3.8 years; the average age of loss of walking is 13.8 years; the average age of death is 33 years.

Diagnosis/testing.

The diagnosis of HMSN/ACC is established in a proband with suggestive findings and biallelic pathogenic variants in SLC12A6 identified by molecular genetic testing.

Management.

Treatment of manifestations: Walking aids such as canes or walkers are required. As the disease progresses, orthoses for upper and lower limbs and physiotherapy are needed to prevent contractures. Early developmental/educational intervention addresses cognitive delays. Depending on severity, individuals with HMSN/ACC usually require corrective surgery for scoliosis. Neuroleptics may be used to treat psychiatric manifestations, usually during adolescence.

Surveillance: Monitor in the early teens for scoliosis and in the late teens for psychiatric manifestations.

Genetic counseling.

HMSN/ACC is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic. Once the SLC12A6 pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members and prenatal and preimplantation genetic testing are possible.

Diagnosis

Consensus diagnostic criteria for hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) have not been established.

Suggestive Findings

Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) should be suspected in individuals with the following clinical, electrophysiologic, and neuroimaging findings, and family history [Dupré et al 2003].

Clinical findings

Severe progressive sensorimotor neuropathy with areflexia
Developmental delay / intellectual disability ranging from mild to severe

Electrophysiology

Sensory nerve action potentials cannot be recorded at the median, ulnar, or sural nerves even in children in their first year of life.
Compound motor action potentials usually show diminished amplitudes.
Nerve conduction velocities for the median, ulnar, and tibial nerves are variable.
Needle electromyography may show mild signs of active denervation (e.g., fibrillation potentials).

Neuroimaging

Brain MRI showing complete agenesis of the corpus callosum in 60% of individuals (Figure 1A, 2A), partial agenesis in 10%, and normal corpus callosum in 30% (Figure 1B, 2B)
Mild cortical or cerebellar atrophy at a later age

Figure 1.

Sagittal T₁-weighted MRI A. Complete agenesis of the corpus callosum

Figure 2.

Axial T₁-weighted MRI A. Agenesis of the corpus callosum with parallelism of the ventricles

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in SLC12A6 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic SLC12A6 variants of uncertain significance (or identification of one known SLC12A6 pathogenic variant and one SLC12A6 variant of uncertain significance) does not establish or rule out a diagnosis of this disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of HMSN/ACC has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

Single-gene testing. Sequence analysis of SLC12A6 is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.

Note: In individuals of French Canadian origin who have the typical phenotype, targeted analysis for the c.2436+1delG pathogenic variant can be performed first, followed by sequence analysis if only one or no variant is identified.

An agenesis of the corpus callosum panel, an intellectual disability panel, or a comprehensive neuropathy panel (multigene panels that include SLC12A6 and other genes of interest; see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum

Clinical Characteristics

Clinical Description

Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) is both a neurodevelopmental disorder (with variable degrees of dysgenesis of the corpus callosum and mild-to-severe intellectual disability) and a neurodegenerative disorder (severe progressive sensorimotor neuropathy).

The neurologic findings of HMSN/ACC in 64 individuals (ages 2 to 34 years) in the French Canadian population reported by Mathieu et al [1990] are summarized in Table 2, with additional information from Larbrisseau et al [1984], Salin-Cantegrel et al [2007], and Auer et al [2016].

Table 2.

Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum: Select Features

Progressive motor and sensory neuropathy

Reflexes invariably absent from infancy
Hypotonia invariably present in the first year of life
Progressive distal and proximal symmetric limb weakness
Muscle atrophy
Diffuse limb tremor (probably secondary to polyneuropathy)
Contractures
Loss of sensation to touch and pinprick in a glove and stocking distribution; easier to evaluate in older children

The average age of onset for sitting alone is 2.1 years, for standing is more than two years, for walking is 3.8 years, and average age of loss of ability to walk is 13.8 years.

Cognitive function. The Taft clinical classification uses an IQ test to rank individuals in four categories: normal intelligence (IQ >75), mild intellectual disability (IQ = 50-75), moderate intellectual disability (IQ = 25-50), and severe intellectual disability (IQ <25). Individuals with mild intellectual disability can achieve five to six years of elementary school and live independently. Individuals with moderate intellectual disability can help with activities of daily living but require supervision on a daily basis. Individuals with severe intellectual disability require assistance for daily living and supervision but may be able to take care of some routine daily needs. The range of intelligence of individuals with HSMN/ACC is normal IQ to severe intellectual disability.

Psychotic episodes. Mathieu et al [1990] reported that after age 15 years, 39% (25/64) developed "psychotic episodes" characterized by paranoid delusions, depressive states, visual hallucinations, auditory hallucinations, or "autistic-like" features.

Life expectancy. Average age of death is 33 years and is usually related to respiratory insufficiency [Larbrisseau & Sarnat 2017].

Other

Lumbar puncture usually reveals mild elevation of CSF proteins [Dupré et al 2003].
Sural nerve biopsy shows an almost total lack of large myelinated fibers, signs of axonal loss (ovoids of Wallerian degeneration), and some enlarged axons that on electron microscopy show decreased density of neurofilaments. Isolated fibers may have disproportionately thin myelin sheaths, suggesting that the axoplasm is swollen. Electron microscopy may show decreased packing density of neurofilaments, without signs of their degradation [Dupré et al 2003, Auer et al 2016].
Note: Sural nerve biopsy is unnecessary to confirm the diagnosis, now that molecular genetic testing is possible.
EEG may be normal or with epileptiform abnormalities [Dupré et al 2003, Salin-Cantegrel et al 2007].
Muscle biopsy shows nonspecific signs of chronic denervation atrophy [Dupré et al 2003, Auer et al 2016].

Autopsy examination. The hallmark is swollen axons in cranial nerve samples (especially cranial nerves 3 and 7), as well as in the dorsal and ventral nerve roots. Swollen axons can also be scattered in the white matter. The brain shows either no agenesis of the corpus callosum (ACC), partial ACC, or complete ACC with preservation of Probst bundle [Dupré et al 2003, Auer et al 2016].

Genotype-Phenotype Correlations

The data from affected individuals are insufficient to establish genotype-phenotype correlations.

Nomenclature

HMSN/ACC may also be referred to as Charlevoix disease.

Prevalence

In the French Canadian population of the Saguenay and Lac-St-Jean regions of Quebec, Canada, the overall incidence of HMSN/ACC is 1:2,117 live births; the carrier rate is 1:23 inhabitants due to the c.2436+1delG (also known as c.2436delG) founder variant. Otherwise, HMSN/ACC is extremely rare worldwide. Three pairs of sibs (of Italian, Mexican, and Turkish origin) have been reported to have molecularly confirmed HMSN/ACC.

Genetically Related (Allelic) Disorders

No phenotypes other than those discussed in this GeneReview are known to be associated with mutation of SLC12A6.

Differential Diagnosis

Table 3.

Autosomal Recessive Neurodegenerative Disorders in the Differential Diagnosis of Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum

Management

Consensus clinical management recommendations for hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) have not been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum

Treatment of Manifestations

Care is best provided by a multidisciplinary team that comprises a pediatrician or pediatric neurologist, developmental pediatrician, psychiatrist, orthopedist, physiotherapist, and occupational therapist.

Table 5.

Treatment of Manifestations in Individuals with Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

IEP services:
- An IEP provides specially designed instruction and related services to children who qualify.
- IEP services will be reviewed annually to determine whether any changes are needed.
- Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
- Vision consultants should be a part of the child's IEP team to support access to academic material.
- PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
- As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Surveillance

Table 6.

Recommended Surveillance for Individuals with Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one SLC12A6 pathogenic variant based on family history).
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an SLC12A6 pathogenic variant and to allow reliable recurrence risk assessment. (De novo variants are known to occur at a low but appreciable rate in autosomal recessive disorders [Jónsson et al 2017].)
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

If both parents are known to be heterozygous for an SLC12A6 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Due to the severity of the disorder, individuals with HMSN/ACC do not reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an SLC12A6 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the SLC12A6 pathogenic variants in the family.

See Related Genetic Counseling Issues, Population screening for information about carrier testing in individuals who do not have a family history of HMSN/ACC.

Related Genetic Counseling Issues

Family planning

The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

Population screening. Individuals with a genealogic link to regions with high HMSN/ACC carrier rates may choose to have carrier testing for the c.2436+1delG French Canadian HMSN/ACC founder variant (see Prevalence and Table 7).

Prenatal Testing and Preimplantation Genetic Testing

Once the SLC12A6 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

National Organization for Disorders of the Corpus Callosum
Email: info@nodcc.org
www.nodcc.org
Hereditary Neuropathy Foundation
Phone: 855-435-7268 (toll-free); 212-722-8396
Fax: 917-591-2758
Email: info@hnf-cure.org
www.hnf-cure.org
Muscular Dystrophy Canada
Canada
Phone: 800-567-2873
Email: info@muscle.ca
muscle.ca
National Institute of Neurological Disorders and Stroke (NINDS)
PO Box 5801
Bethesda MD 20824
Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)
Agenesis of the Corpus Callosum Information Page

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum: Genes and Databases

Table B.

OMIM Entries for Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum (View All in OMIM)

Molecular Pathogenesis

SLC12A6 encodes solute carrier family 12 member 6 (KCC3) whose protein structure includes:

12 putative membrane-spanning helices with large NH2 and COOH termini;
A large extracellular loop between transmembrane domains 7 and 8 with five potential sites for N-linked glycosylation;
Two consensus cAMP-dependant protein kinase phosphorylation sites;
Four consensus protein kinase C phosphorylation sites in the COOH terminus.

KCC3, a cell cotransporter of the peripheral and central nervous system throughout neurologic development and adulthood, is necessary for the transport of chloride and potassium for the regulation of axonal cell volume [Delpire & Kahle 2017, Flores et al 2019]. Absence of KCC3 alters maintenance of homeostasis of the membrane threshold, leading to neuronal degeneration [Flores et al 2019].

KCC3 is also involved in the precise propagation of the paranodal action potential [Sun et al 2016]. This is consistent with brain autopsies of individuals with HMSN/ACC in whom regenerative clusters in the peripheral nervous system indicate ongoing degeneration [Auer et al 2016].

Although both loss of function and gain of function of KCC3 can cause peripheral neuropathy, gain of KCC3 function causes peripheral neuropathy without abnormalities of the corpus callosum or cognitive abilities [Flores et al 2019].

Studies on mice lacking Kcc3 have demonstrated a normal-appearing corpus callosum, suggesting that Kcc3 may not play a role in either embryonic or postnatal formation of the corpus callosum in mice [Shekarabi et al 2012].

Mechanism of disease causation. Loss of function

Table 7.

Notable SLC12A6 Pathogenic Variants

Chapter Notes

Acknowledgments

This work was supported by La Fondation des Jumelles Coudé and the Canadian Institute of Health Research.

Additionally, the authors would like to acknowledge the very significant contributions of Dr Jean Mathieu and Dr Jean-Pierre Bouchard to the understanding of HMSN/ACC, which have been the cornerstone of its phenotypic and genotypic characterization in the last decade.

Author History

Jean-Denis Brisson, MD, FRCP(C) (2020-present)
Nicolas Dupré, MD, MSc, FRCP(C) (2006-present)
Claudie Gauvreau, MD, MSc (2020-present)
Heidi C Howard, PhD; Radboud University Medical Center (2006-2020)
Guy A Rouleau, MD, PhD, FRCP(C); McGill University (2006-2020)

Revision History

17 September 2020 (bp) Comprehensive update posted live
12 June 2014 (me) Comprehensive update posted live
18 June 2009 (me) Comprehensive update posted live
2 February 2006 (me) Review posted live
2 September 2005 (gr) Original submission

References

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Publication Details

Author Information and Affiliations

Claudie Gauvreau, MD, MSc

Neurology resident, CHU de Québec – Enfant-Jésus
Laval University
Quebec City, Canada

Email: ac.lavalu@2.uaervuag.eidualc

Jean-Denis Brisson, MD, FRCP(C)

Neurologist, Groupe de Recherche Interdisciplinaire sur les Maladies Neuromusculaires
Centre Intégré Universitaire de Santé et de Services Sociaux du Saguenay-Lac-Saint-Jean;
Sherbrooke University
Quebec, Canada

Email: ac.ekoorbrehsu@nossirb.sined-naej

Nicolas Dupré, MD, MSc, FRCP(C)

Neurologist, Neurogenetics Clinic
Department of Neurological Sciences
CHA – Enfant-Jésus
Quebec City, Canada

Email: ac.cebeuqeduhc@erpud.salocin

Publication History

Initial Posting: February 2, 2006; Last Update: September 17, 2020.

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NLM Citation

Gauvreau C, Brisson JD, Dupré N. Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum. 2006 Feb 2 [Updated 2020 Sep 17]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

Gene ¹	Method	Proportion of Pathogenic Variants ² Detectable by Method
SLC12A6	Sequence analysis ³	>90% ^4, 5
SLC12A6	Gene-targeted deletion/duplication analysis ⁶	1 reported ⁷

Feature		% of Persons w/Feature	Comment
Motor & sensory neuropathy		100%
Cranial nerve involvement	Ptosis	33%-59%	Symmetric or asymmetric
	Gaze palsy	13%-30%
	Horizontal nystagmus	20%
	Facial weakness	34%-100%	Symmetric or asymmetric; may be assoc w/hemifacial atrophy
Cognitive function	Normal	8%	Based on Taft clinical classification to stratify cognitive function in 53 persons ¹
	Mild ID	49%
	Moderate ID	40%
	Severe ID	4%
Psychotic episodes		39% (25/64)	After age 15 yrs ¹
Scoliosis		86%	Average onset age 10.4 yrs
Pulmonary restrictive syndrome		Unknown	Related to scoliosis & axonal loss affecting respiratory muscles ²
Contractures		59%	MCP joint (flexion) contracture
		50%	Valgus foot deviation
		47%	Early Achilles tendon retraction
		31%	Varus foot deviation
Seizures		17%	Generalized, absence, or focal seizures ³
Tremor		25%

Gene(s)	DiffDx Disorder	Clinical Characteristics	Features of DiffDx Disorder Distinguishing It from HMSN/ACC
EGR2 FGD4 FIG4 GDAP1 MTMR2 NDRG1 PRX SBF1 SBF2 SH3TC2	Autosomal recessive HMSN (Previously CMT4; see CMT Overview.)	Severe early-onset neuropathy	Absence of ID & dysgenesis of CC
PLA2G6	Classic infantile neuroaxonal dystrophy (INAD) (See PLA2G6 Neurodegeneration.)	Classic INAD: typical onset age 6 mos to 3 yrs w/developmental regression, hypotonia, progressive psychomotor delay, & progressive spastic tetraparesis; strabismus, nystagmus, & optic atrophy common; ± partial ACC Rapid disease progression: many affected children never learn to walk or lose this ability shortly after attaining it; severe spasticity, progressive cognitive decline, & visual impairment typically → death in 1st decade. Atypical NAD: see footnote 1.	Faster & more severe regression of motor skills Spasticity
ARSA	Arylsulfatase A deficiency (metachromatic leukodystrophy [MLD])	Infantile- & early-juvenile-onset MLD present w/CNS &/or peripheral nervous system manifestations; affected persons eventually lose motor & intellectual functions. Disease course is ~3-10 yrs in late-infantile-onset MLD & ~20 yrs in juvenile-onset MLD; death is most commonly from pneumonia or other infection.	Absence (typically) of ACC Leukodystrophy
GAN	Giant axonal neuropathy	Presents w/severe peripheral motor & sensory neuropathy in infancy; evolves into CNS impairment (ID, seizures, cerebellar signs, & pyramidal tract signs); pathologic hallmark is "giant axons" assoc w/massive disorganization & aggregation of neurofilaments. Most persons become wheelchair dependent in 2nd decade of life & eventually bedridden w/severe polyneuropathy, ataxia, & dementia; death usually occurs in 3rd decade.	Absence (typically) of ACC Atrophy of CC in some affected persons
SPG11	Spastic paraplegia 11	Progressive spasticity & weakness of lower limbs frequently assoc w/mild ID w/learning difficulties in childhood &/or progressive cognitive decline, peripheral neuropathy, pseudobulbar involvement, & ↑ reflexes in upper limbs. Less frequent findings: cerebellar signs (ataxia, nystagmus, saccadic pursuit), retinal degeneration, pes cavus, scoliosis, parkinsonism Onset occurs mainly in infancy or adolescence; most affected persons become wheelchair bound 1-2 decades after disease onset.	Hyperreflexia of upper limbs & spasticity Thin CC in some affected persons
GALC	Krabbe disease (GALC deficiency, globoid cell leukodystrophy)	Infantile form presents before age 12 mos w/extreme irritability, axial hypotonia, spasticity, loss of acquired milestones, & peripheral neuropathy; average age at death is 24 mos. Late-onset form presents after age 12 mos (childhood-7th decade) & may present as DD or regression; disease course is variable & may be assoc w/spastic paraparesis, peripheral neuropathy, seizures, & vision loss.	Spastic paraparesis (in late onset form) Thin CC in some affected persons

System/Concern	Evaluation	Comment
Motor & sensory neuropathy	Neurologic exam	Obtain EEG. Consider MRI if not previously performed.
Seizures	Neurologic exam	Obtain EEG. Consider MRI if not previously performed.
Musculoskeletal	Orthopedics / physical medicine & rehab / PT & OT eval	To incl assessment of: Gross motor & fine motor skills Possible contractures (esp Achilles tendon) Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Mobility, self-help skills, ADL, & need for adaptive devices
Scoliosis	Orthopedics & pulmonary medicine	Baseline eval for scoliosis Baseline pulmonary function assessment given ↑ risk for restrictive lung disease
Extraocular muscle involvement	Ophthalmologic exam	Assess for ptosis, esotropia or exotropia, gaze palsy, & nystagmus.
Developmental delay / Intellectual disability	Developmental assessment	To incl motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education / community & social activities
Psychotic episodes	Obtain history of possible events.	When concerns, refer for psychiatric eval.
Genetic counseling	By genetics professionals ¹	To inform affected persons & their families re nature, MOI, & implications of HMSN/ACC to facilitate medical & personal decision making
Family support & resources	Assess need for: Community or online resources such as Parent to Parent; Social work involvement for parental support; Home nursing referral.

Manifestation/Concern	Treatment	Considerations/Other
Seizures	Standardized treatment w/ASM by experienced neurologist	Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Valproate may also be beneficial for behavioral problems. Education of parents/caregivers ¹
Extraocular muscle involvement	Standard treatment(s) per ophthalmologist
Musculoskeletal	Orthopedics / physical medicine & rehab / PT & OT	Regular physiotherapy to maximize mobility & ↓ risk for later orthopedic complications (e.g., hand & foot contractures, scoliosis) Walking aids incl canes or walkers when appropriate Use of orthoses for upper & lower limbs as needed Durable medical equipment & positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers) Disability parking placard for caregivers
Scoliosis	Orthopedics	Depending on degree of severity, scoliosis usually requires surgical correction.
Scoliosis	Pulmonary medicine	Intervention per standard care
Developmental delay / Intellectual disability	See Developmental Delay / Intellectual Disability Management Issues.
Psychotic episodes	Psychiatric eval	Low-dose neuroleptics may be useful.
Family support/ resources	Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.

System/Concern	Evaluation	Frequency
Motor & sensory neuropathy	Neurologic exam	Annual
Seizures	Evaluate response to current treatment.	Per treating neurologist
Seizures	Assess for new-onset seizures	At each visit
Musculoskeletal	Per treating PT/OT	Annual or biannual
Scoliosis	Per treating orthopedist	Esp in early teen yrs when significant scoliosis is likely to appear Annual or biannual
Restrictive lung disease	Monitor for evidence of respiratory insufficiency.	As needed if symptoms are present
Extraocular muscle involvement	Ophthalmologic exam	Per treating ophthalmologist
Developmental delay / Intellectual disability	Monitor developmental progress & educational needs.	At each visit
Psychotic episodes	Evaluate response to current treatment.	As needed Refer to psychiatrist.
Psychotic episodes	Evaluate for new-onset psychosis & paranoid delusions.	At each visit, esp in late teens when onset is typical

218000	AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY; ACCPN
604878	SOLUTE CARRIER FAMILY 12 (POTASSIUM/CHLORIDE TRANSPORTER), MEMBER 6; SLC12A6