Leukodystrophies and Related Disorders

White Matter Disorders

• These are disorders affecting the CNS (and sometimes PNS) white matter.
• Differentiate them from other acquired processes.
• Endocrine dysfunction (congenital and acquired thyroid and adrenal).
• Nutritional factors (Vitamin B12 deficiency).
• Acquired disorders include periventricular leukomalacia, toxic or infectious process.
• Clinical presentation includes progressive spasticity, bulbar symptoms, and preserved cognition.

Leukodystrophies

• Heritable myelin disorders affecting CNS (and sometimes PNS) white matter.
• Differentiate from other acquired processes.
• Nutritional factors: Vitamin B12 deficiency.
• Endocrine dysfunction: congenital and acquired thyroid and adrenal dysfunction
• Acquired: periventricular leukomalacia, toxic or infectious process.
• Clinical findings: progressive spasticity, bulbar symptoms, and preserved cognition.

Rads

• Two main types
  • Hypomyelinating: Hyper T2, iso/hyper T1.
  • Demyelinating: Hyper T2, Hypo T1.

Hypomyelinating White Matter Disorders

• Pelizaeus-Merzbacher Disease.
• 4H Syndrome.
• Trichothiodystrophy.
• Cockayne Syndrome.

Hypomyelinating WM Disorders

• Account for 20% of leukodystrophies.
• Characterized by a permanent deficit of myelin.
• Most are autosomal recessive (AR), but some are X-linked (XL) or de novo.
• Clinical presentation includes ataxia, spasticity, and nystagmus.
• Diagnosis is made using MRIs taken 6 months apart in patients older than 12 months to assess myelin development.
• Imaging often shows hyperintense white matter on T2-weighted images and iso/hyperintensity on enhanced T1 images.

Pelizaeus-Merzbacher Disease

• PLP1 gene mutation (Xq22.2), usually a duplication.
• Clinical features include:
  • Pendular nystagmus in infancy, delayed development, axial hypotonia, and dystonia/chorea.
  • Congenital form: congenital stridor, feeding difficulties, and profound hypotonia.
• Associated with X-linked spastic paraplegia type 2 (SPG2).
• Mutations in PLP1 can cause progressive spasticity.
• Complicated form includes spasticity, nystagmus, ataxia, dysarthria, and mild cognitive impairment.

Pelizaeus-Merzbacher Disease (Imaging)

• MRI of a 23-month-old patient shows homogeneous hyperintense white matter on axial T2-weighted images, indicating profound hypomyelination.
• There is a lack of myelin in the cerebellum and a thin corpus callosum.

Pelizaeus-Merzbacher-like disease

• GJC2 gene mutation (connexin 47), autosomal recessive (AR) inheritance.
• Clinical features: nystagmus, hypotonia, ataxia, and spasticity.
• MRI shows brainstem signal abnormalities and atrophy.
• Milder than Pelizaeus–Merzbacher disease.

4H Syndrome

• POLR3A or POLR3B gene mutations, AR inheritance.
• Clinical features include:
  • Normal development until 18 months, with frequent falls, ataxia, dysmetria, and nystagmus.
  • Progressive motor decline and less impaired cognition.
  • Hypodontia or disordered eruption of teeth, and natal teeth.
  • Low FSH/LH levels.
• MRI: cerebellar atrophy.
• Treatment includes growth hormone if deficient, and hormone supplementation to induce puberty and prevent osteoporosis.

Oculodentodigital dysplasia

• GJA1 gene (connexin 43), autosomal recessive (AR).
• Diagnosis is based on dysmorphic features.
• Features include microphthalmia, dental anomalies, and syndactyly.
• Mild neuro symptoms include ataxia and spasticity.

Salla Disease

• A sialic acid storage disorder.
• SLC17A5 gene, autosomal recessive (AR)
• Sialic acid accumulates in lysosomes.
• Clinical features include:
  • Normal early development, followed by hypotonia, nystagmus, spasticity, and dystonia at 6 months.
• Coarse facial features.
• MRI: thin corpus callosum, cerebellar atrophy.
• MRS: high NAA peak (sialic acid peak).

Cockayne Syndrome

• Gene mutations in CSA, CSB, XP, or XPD.
• Type I
  • Presents in the first year of life with failure to thrive (FTT), microcephaly, and bird-like face.
  • Microcephaly, contractures, large hands and feet, dental caries, cutaneous photosensitivity, and cataracts are common.
• Type II: more severe; IUGR, contractures, hypotonia, and severe SQ fat loss
• MRI: basal ganglia calcifications.

Trichothiodystrophy

• Gene mutations in CSA, CSB, XPB, or XPD.
• Clinical features include:
  • Thin, brittle, kinky hair and hair loss with fever.
  • Dystrophic nails, cutaneous photosensitivity, and ichthyosis.
  • Neurological features: developmental delay, cognitive impairment, spasticity, and cataracts.

SOX10-associated disorders

• SOX10 mutation, 22q13 gene.
• Clinical features: white hair lock, hypomelanotic spots, and sensorineural hearing loss (SNHL).
• Hirschsprung disease.
• Congenital arthrogryposis multiplex.

White Matter Disorders with Demyelination

• Alexander disease
• X-linked adrenoleukodystrophy
• Metachromatic leukodystrophy

Alexander Disease

• GFAP mutation, chromosome 17, usually autosomal dominant (AD).
• Rosenthal fibers on biopsy.
• Type I
  • Presents before 4 years of age.
  • Macrocephaly, delayed milestones, seizures, and bulbar symptoms.
  • Hydrocephalus.
• Weakness, spasticity, and regression.
• MRI: frontal predominant WM involvement, basal ganglia/brainstem involvement; enhancing areas present in T2.
• Type II
  • Presents after 4 years of age, milder presentation of fine motor impairment
  • Dysphagia, dysphonia, palatal myoclonus, Guillain-Barré syndrome.
  • Dysautonomia and sleep apnea are possible.
  • MRI is atypical: posterior/brainstem predominant, with supratentorial WM spared.
• X-linked form, but most patients have AD form

X-linked Adrenoleukodystrophy (X-ALD)

• ABCD1 gene, peroxisomal membrane transporter, X-linked (XL).
• Childhood presentation in school-aged boys.
• Behavioral and cognitive changes (e.g., ADHD).
• Motor difficulties, altered perception of speech, vision and hearing problems, and spasticity.
• Adrenal insufficiency.
• Adrenomyeloneuropathy (AMN): adult-onset.
• Elevated very long-chain fatty acids (VLCFAs).
• MRI: occipital predominant; enhancement with hyperintense white matter, hypointense on T1.
• Hematopoietic stem cell transplant (HSCT) may be a treatment option.
• Hydrocortisone used for Addison Syndrome.
• Lorenzo’s oil to lower VLCFAs (not recommended anymore).

Metachromatic Leukodystrophy (MLD)

• ARSA gene, encoding arylsulfatase A.
• Chromosome 22q, autosomal recessive (AR).
• Late infantile
  • Presents by 2 years with gait disturbance, ataxia, dysarthria, motor regression and peripheral neuropathy
• Tonic spasms, seizures, spasticity, profound hearing loss, cherry-red spot.
• Juvenile: age 2-16 years.
• Adult: motor impairment, peripheral neuropathy, neuropsych symptoms, and progressive cognitive decline.
• MRI: reveals confluent periventricular changes sparing arcuate U-fibers; radial stripes (tigroid appearance), and butterfly pattern common.
• Elevated urinary sulfatide levels and decreased levels of arylsulfatase A in blood.
• Tx: cholecystectomy for prevention of cancer and polyps.
• HSCT used in early cases

Krabbe Disease (Globoid Cell Leukodystrophy)

• GALC gene, chromosome 14q31, accounts for deficiency of galactosylceramidase, AR inheritance
• Infantile-onset (6 months): irritability, hypertonia, peripheral nerve involvement.
• Stages II & III: opisthotonic posture, optic atrophy, seizures, spasticity, blindness, decerebrate posturing.
• Late-onset (>6 months): vison loss, spasticity, developmental regression, juvenile (>=4 years) & adult onset gait dysfunction, spastic paraparesis, cognitive/behavioral decline and seizures; demyelinating peripheral neuropathy.
• Slower progression than infantile-onset.
• MRI: globoid cells in affected white matter, hyperdense thalami, caudate, and cerebellum.
• CSF: increased protein; NCS (nerve conduction studies): demyelinating peripheral neuropathy (prolonged motor conduction velocities).
• Low GALC enzyme activity in fibroblasts.
• Treatment: HSCT in very early stages is crucial.

Canavan Disease

• ASPA gene, autosomal recessive (AR gene), Ashkenazi Jewish.
• Deficiency of aspartoacylase.
• Clinical
  • Presents at 3-6 months
  • Includes hypotonia, regression, irritability, macrocephaly, spasticity, seizures, optic atrophy, and choreiform movements.
• Congenital variant = rapid encephalopathy
• Ix: high NAA peak on MRS and in urine.
• Path: spongy degeneration.
• MRI: confluent subcortical white matter involvement; sparing of globus pallidus and thalami.
• Caudate and putamen are spared.

Vanishing White Matter Disease

• EIF2B1-5 gene mutation (AR).
• Infantile onset: deterioration after physiologic stress (fever, falls, fright); presents with acute episodes of motor dysfunction, hypotonia, ataxia, and coma.
• Connatual form: encephalopathy, ovarian dysgenesis, cataracts, hepatosplenomegaly present,
• Adult onset: progressive spastic paraparesis.
• MRI: shows diffuse supratentorial white matter abnormality with cystic changes; diffuse white matter changes resembling fluid or CSF; basal ganglia spared.

Megalencephalic Leukoencephalopathy with Subcortical Cysts (MLC)

• Mutation in gene encoding MLC1 protein, HEPACAM.
• Clinical: macrocephaly, temporal lobe subcortical cysts, spastic ataxia, and epilepsy.
• MRI: swollen subcortical white matter, with diffuse signal abnormality; preserved central structures (corpus callosum, internal capsules, brainstem)
• Tx: avoidance of head trauma and prompt treatment of status epilepticus.

Calcifying Leukoencephalopathies (Aicardi-Goutières Syndrome)

• Multiple genes (TREX1, ADAR1, SAMHD1, IFIH1), autosomal recessive.
• Clinical
  • Subacute encephalopathy, dystonia, spasticity, and microcephaly.
  • Mimics TORCH infections in neonates (e.g., hemolytic anemia, thrombocytopenia, transaminitis, and seizures).
• Ix: elevated CSF alpha interferon.
• MRI: intracranial calcifications (basal ganglia/white matter), retinal vasculopathy with cerebral leukodystrophy (RVCL).
• Associated with migraine, Raynaud’s phenomenon, stroke and TREX1-associated lupus.

Others

• Cockayne Syndrome: bandlike intracranial calcification, simplified gyration, and polymicrogyria.
• Leukoencephalopathy with calcifications and cysts.
• Cerebroretinal microangiopathy with calcifications and cysts (CRMCC).
• Cadasil: cerebral AD arteriopathy with subcortical infarcts and leukoencephalopathy. NOTCH3 mutation; migraines, progressive CVS, and cognitive decline.

Mitochondrial Leukoencephalopathies

• MNGIE (mitochondrial neurogastrointestinal encephalopathy)
• Progressive GI dysmotility, ophthalmoplegia, and hearing loss.
• Demyelinating peripheral neuropathy.
• Pyruvate carboxylase deficiency.
• Infants with lactic acidosis, developmental delay, and seizures.
• Glutaric acidemia type II (multiple acylCoA dehydrogenase deficiency).
• Episodic hypoglycemia, acidosis, coma, and cardiomyopathy.
• Sweaty feet odour.

General Treatment

• Spasticity: botulinum toxin, intrathecal baclofen, selective dorsal rhizotomy.
• Nutritional support: G-tube.
• Infection prevention and treatment (prophylactic antibiotics).
• Bladder and bowel dysfunction management.
• Orthopedic issues (e.g., hip dislocation).
• Calcium and vitamin D supplementation.
• Neuropathic pain: amitriptyline, gabapentin.
• Irritability and sleep issues: melatonin.
• Sialorrhea: glycopyrrolate, botulinum toxin.
• Epilepsy: AEM.
• Adequate communication.

Adult Onset Leukoencephalopathies

• Metachromatic leukodystrophy
• Adult-onset Alexander disease
• Adult-onset X-linked adrenoleukodystrophy
• Adult-onset Krabbe disease
• Vanishing white matter disease

Differential Diagnosis for Macrocephaly

• Canavan disease
• Alexander disease
• Megalencephalic leukoencephalopathy with subcortical cysts (MLC)
• Hemimegalencephaly syndromes
• Hypomelanosis of Ito
• Neurofibromatosis type 1 (NF1)
• Glutaric acidemia type 1

Differential Diagnosis for Frontal Predominance

• Alexander disease
• Metachromatic leukodystrophy
• X-ALD frontal variant

Cerebrotendinous Xanthomatosis

• AR, CYP27A1 gene.
• Behavioral abnormalities, progressive cognitive decline, cerebellar signs, palatal myoclonus, and skin changes (tendon xanthomas).
• MRI: signal abnormality in dentate nucleus, substantia nigra, and globus pallidus.
• Dx: high serum cholestanol.

Polyglucosan Body Disease

• GBE1 gene, autosomal recessive (AR).
• Allelic to glycogen storage disorder IV (GSD IV).
• Clinical features include ataxia and parkinsonism, onset in 60s.
• UMN and LMN features, distal sensory neuropathy, and progressive cognitive deficits.
• MRI shows confluent white matter abnormalities.

Autosomal dominant leukodystrophy with autonomic disease

• LMNB1 gene, autosomal dominant (AD).
• Slowly progressive ataxia, cognitive impairment, and autonomic dysfunction.
• Urinary urgency, constipation, impotence, and postural hypotension.
• MRI shows confluent white matter changes.