Leukodystrophies and Related Disorders
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Questions and Answers

What distinguishes leukodystrophies from other acquired white matter disorders?

Leukodystrophies are heritable myelin disorders affecting CNS white matter, unlike acquired processes which are often due to factors like endocrine dysfunction or nutritional deficiencies.

What are the MRI characteristics seen in hypomyelinating white matter disorders?

Hypomyelinating white matter disorders typically show hyperintense signals on T2-weighted MRI and iso/hyperintense on T1-weighted images.

Describe the key clinical features of Pelizaeus-Merzbacher Disease.

Key clinical features include pendular nystagmus in infancy, axial hypotonia, feeding difficulties, and progressive spasticity.

What genetic mutation is associated with Pelizaeus-Merzbacher Disease?

<p>Pelizaeus-Merzbacher Disease is primarily associated with PLP1 mutations located on chromosome Xq22.2.</p> Signup and view all the answers

What triad of symptoms defines 4H Syndrome?

<p>The triad of symptoms in 4H Syndrome includes hypomyelination, hypodontia, and hypogonadotropic hypogonadism.</p> Signup and view all the answers

What distinguishes Pelizaeus-Merzbacher-like disease from Pelizaeus-Merzbacher Disease?

<p>Pelizaeus-Merzbacher-like disease, caused by GJC2 gene mutations, is usually milder than Pelizaeus-Merzbacher Disease, although it shares symptoms like nystagmus and hypotonia.</p> Signup and view all the answers

What is the significance of identifying the age of onset in 4H Syndrome?

<p>In 4H Syndrome, normal development until 18 months followed by frequent falls and motor decline indicates a specific pattern of progression that is critical for diagnosis.</p> Signup and view all the answers

How does the treatment for 4H Syndrome address hormonal deficiencies?

<p>Treatment for 4H Syndrome may include growth hormone therapy if deficient and hormone supplementation to induced puberty and prevent osteoporosis.</p> Signup and view all the answers

What gene is associated with Metachromatic Leukodystrophy (MLD) and what does it encode?

<p>The ARSA gene, which encodes arylsulfatase A.</p> Signup and view all the answers

List two clinical symptoms of late infantile MLD.

<p>Gait disturbance and motor regression.</p> Signup and view all the answers

What MRI findings are characteristic of Metachromatic Leukodystrophy?

<p>Confluent periventricular changes with sparing of the arcuate U-fibers and a tigroid appearance.</p> Signup and view all the answers

What is the main enzymatic deficiency in Krabbe Disease?

<p>A deficiency of galactosylceramidase due to GALC gene mutation.</p> Signup and view all the answers

What are the observed symptoms during Stage I of infantile Krabbe Disease?

<p>Irritability and hypertonia with peripheral nerve involvement.</p> Signup and view all the answers

Describe a key laboratory finding in the diagnosis of Krabbe Disease.

<p>Increased protein levels in the cerebrospinal fluid (CSF).</p> Signup and view all the answers

What genetic mutation causes Sjogren-Larsson syndrome and what are its key clinical features?

<p>Mutation in the FALDH gene leading to ichthyosis, progressive spasticity, and intellectual disability.</p> Signup and view all the answers

What is the recommended treatment for early cases of Metachromatic Leukodystrophy?

<p>Hematopoietic stem cell transplant (HSCT).</p> Signup and view all the answers

What are the key clinical features of Salla Disease, particularly before and after 6 months of age?

<p>Before 6 months, development is normal; after that, features include hypotonia, nystagmus, spasticity, dystonia, and seizures.</p> Signup and view all the answers

What distinguishes Type I and Type II Cockayne Syndrome in terms of clinical manifestation?

<p>Type I presents with failure to thrive, microcephaly, and a bird-like face, while Type II is more severe with intrauterine growth restriction (IUGR), hypotonia, and significant contractures.</p> Signup and view all the answers

Describe the genetic mutation and one clinical manifestation associated with SOX10-associated disorders.

<p>These disorders are linked to mutations in the SOX10 gene on chromosome 22q13, leading to features like white hair locks or hypomelanotic spots.</p> Signup and view all the answers

Enumerate the neurological symptoms associated with Alexander Disease.

<p>Symptoms include progressive ataxia, spasticity, fine motor impairment, dysphagia, and dysautonomia.</p> Signup and view all the answers

What MRI findings are characteristic of X-linked Adrenoleukodystrophy in children?

<p>MRI shows occipital predominance with hyperintense T2 and hypointense T1 signals, often with a rim of enhancement.</p> Signup and view all the answers

What types of dental and cutaneous features are characteristic of Trichothiodystrophy?

<p>Trichothiodystrophy is characterized by dystrophic nails, cutaneous photosensitivity, and ichthyosis.</p> Signup and view all the answers

What are the primary symptoms of microphthalmia as a smorphic feature?

<p>Microphthalmia is characterized by abnormally small eyes, often associated with dental anomalies and syndactyly.</p> Signup and view all the answers

How does the clinical presentation of Salla Disease relate to the accumulation of sialic acid?

<p>The accumulation of sialic acid in lysosomes leads to symptoms like hypotonia, spasticity, and seizures as observed in affected children.</p> Signup and view all the answers

What are the key clinical features associated with neuroichthyosis syndromes?

<p>Key features include intellectual disability, spastic diplegia, congenital ichthyosis, cognitive impairment, mild to moderate dysarthria, and epilepsy in one-third of cases.</p> Signup and view all the answers

How is Canavan Disease genetically characterized, and what are its predominant clinical manifestations?

<p>Canavan Disease is characterized by a deficiency of aspartoacylase due to mutations in the ASPA gene, presenting with hypotonia, macrocephaly, spasticity, and seizures.</p> Signup and view all the answers

What is the primary genetic mutation involved in Vanishing White Matter Disorders, and what are its clinical implications?

<p>Vanishing White Matter Disorders are caused by mutations in EIF2B1-5, leading to deterioration after physiological stress and various neurological symptoms.</p> Signup and view all the answers

Describe the MRI findings associated with Megalencephalic Leukoencephalopathy with Subcortical Cysts (MLC).

<p>MRI shows swollen subcortical white matter with diffuse signal abnormalities and preserved central structures, as well as subcortical cysts in the temporal and frontal lobes.</p> Signup and view all the answers

What methods are used to diagnose neuroichthyosis syndromes?

<p>Diagnosis depends on the measurement of fatty aldehyde or oxidoreductase complex in fibroblasts obtained from skin biopsies.</p> Signup and view all the answers

What is a common imaging feature of Aicardi-Goutieres Syndrome?

<p>Aicardi-Goutieres Syndrome often presents with characteristic calcifying leukoencephalopathy visible on MRI.</p> Signup and view all the answers

What are the typical clinical presentations of the infantile form of Vanishing White Matter Disorders?

<p>The infantile form presents with deterioration following stress, motor dysfunction, hypotonia, ataxia, and can lead to coma.</p> Signup and view all the answers

What treatments are suggested for managing Megalencephalic Leukoencephalopathy with Subcortical Cysts?

<p>Management includes avoiding head trauma and prompt treatment of status epilepticus.</p> Signup and view all the answers

What are the main clinical features of MNGIE?

<p>Progressive GI dysmotility, ophthalmoplegia, hearing loss, and demyelinating peripheral neuropathy.</p> Signup and view all the answers

What is the most characteristic odor associated with Glutaric acidemia type II?

<p>Sweaty feet odour.</p> Signup and view all the answers

Which treatment is recommended for managing spasticity?

<p>Botulinum toxin, intrathecal baclofen, or selective dorsal rhizotomy.</p> Signup and view all the answers

What is a common clinical feature of CADASIL?

<p>Migraine with aura.</p> Signup and view all the answers

What basal ganglia abnormality is associated with Cerebrotendinous Xanthomatosis?

<p>Signal abnormality in the dentate, substantia nigra, and globus pallidus.</p> Signup and view all the answers

What gene mutation is linked to Polyglucosan body disease?

<p>GBE1 gene mutation.</p> Signup and view all the answers

What condition is characterized by progressive cognitive decline and behavioral changes, alongside skin manifestations?

<p>Cerebrotendinous Xanthomatosis.</p> Signup and view all the answers

Which treatment option is recommended for neuropathic pain?

<p>Amitriptyline or gabapentin.</p> Signup and view all the answers

What are the key clinical features associated with Aicardi-Goutieres Syndrome?

<p>Key clinical features include marked hypotonia, opisthotonic episodes, failure to develop, and febrile episodes.</p> Signup and view all the answers

What MRI findings are indicative of Aicardi-Goutieres Syndrome?

<p>MRI findings typically show calcifications of the basal ganglia, periventricular white matter, and brain atrophy.</p> Signup and view all the answers

Describe the role of elevated CSF alpha interferon in diagnosing certain neurological disorders.

<p>Elevated CSF alpha interferon is a significant finding in Aicardi-Goutieres Syndrome and is often present in the first years of the disease.</p> Signup and view all the answers

What distinguishes Aicardi-Goutieres Syndrome from TORCH infections in neonates?

<p>Aicardi-Goutieres Syndrome presents with specific intracranial calcifications and abnormal white matter without an infectious history.</p> Signup and view all the answers

What disorders are associated with retinal vasculopathy and cerebral leukodystrophy?

<p>These features are representative of an allelic disorder linked to mutations causing retinal vasculopathy with cerebral leukodystrophy (RVCL).</p> Signup and view all the answers

Explain the significance of chilblain skin lesions in Aicardi-Goutieres Syndrome.

<p>Chilblain skin lesions are characteristic cutaneous findings present in about half of the cases of Aicardi-Goutieres Syndrome.</p> Signup and view all the answers

What key diagnostics are used to diagnose Cockayne Syndrome?

<p>Cockayne Syndrome is diagnosed through the presence of bandlike intracranial calcifications, simplified gyration, and polymicrogyria.</p> Signup and view all the answers

Identify two genetic mutations associated with cerebrovascular conditions listed in the content.

<p>NOTCH3 mutations are associated with CADASIL, and HTRA1 mutations are linked to CARASIL.</p> Signup and view all the answers

Study Notes

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.

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Leukodystrophy - updated for questions PDF

Description

This quiz explores the distinguishing features of leukodystrophies, their MRI characteristics, and key clinical aspects of related conditions such as Pelizaeus-Merzbacher Disease and 4H Syndrome. Participants will also learn about genetic mutations, treatment approaches, and diagnostic criteria for these rare neurological disorders.

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