Raili Raininko and Atle Melberg Radiological aspects of genetic disorders with adult-onset CNS symptoms Raili Raininko and Atle Melberg Departments of Radiology and Neuroscience Uppsala University Uppsala, Sweden

Genetic disorders with neurological symptoms: Often pediatric diseases Adult types may occur in some of them - Disorders giving symptoms only in adulthood

Mitochondrial disorders Clinical onset most often in childhood Course: Static - Progressive - Episodes of exacerbation typical Typical symptoms: epilepsy, progressive external ophthalmoplegia (PEO), myopathy, diabetes mellitus Examples: - Leigh syndrome - MELAS (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes) - POLG-1-associated encephalopathy syndromes

POLG-1 mutation (mitochondrial DNA-polymerase gamma) 1. Autosomal recessive - Epilepsy (episodes of focal status epilepticus) - Stroke-like episodes - Ataxia - Ophtalmoplegia - Sensoric neuropathy - (Liver insufficiency ← Valproate)

POLG-1 mutation 2. Dominant form – a different clinical picture PEO, muscular weakness, parkinsonism, ataxia Diagnosis:- Muscle biopsy - mitochondrial DNA analysis for mtDNA deletions - sequencing POLG-1 gene

POLG-1 mutation, autosomal recessive 18-year-old man CT n:o1 CT 2 days later

POLG-1 mutation 4 days from the symptom onset DWI: trace images b= 1000 T2-w FLAIR

POLG-1 mutation Follow-up: 2 mo 3 wk DWI: trace, b=1000 ADC maps T2-w FLAIR

POLG-1 mutation Patient 2 24-year-old man Twin brother succumbed at age of 19 in status epilepticus T2-w SE

Hepatolenticular degeneration = Wilson´s disease Autosomal recessive Hepatic or neurologic symptoms or dementia Tremor, speech disorders, clumsiness, dystonia, personality changes Defect in copper metabolism Diagnosis: - Blood test: caeruloplasmin, copper - Urine test: copper - Liver biopsy - Genetic analysis, ATP7B gene

Wilson´s disease Man, 22 yr, dementia T2-w SE

Wilson´s disease Man, 34 yr, treated T2-w SE

: Polycystic lipomembranous osteodysplasia and sclerosing leukoencephalopathy (PLOSL) = Nasu-Hakola disease : Bone cysts Pain in bones Fractures

Nasu-Hakola disease Later, ~ at age of 30: Symptoms of dementia Death: under age of 50 Autosomal recessive Mutations in DAP12 or TREM2 genes Diagnosis: Clinical + radiological findings

Nasu-Hakola disease Man, 33 yr CT

Nasu-Hakola disease Man 32 yr T2-w SE

Leukodystrophies - Onset most often in childhood Most often recessive inheritance - Also sporadic forms - Some are x-linked Uncommon: Adult-onset forms Dominant inheritance

Metachromatic leukodystrophy (MLD) Types of MLD: - late infantile - juvenile - adult-onset The adult-onset type most often begins with psychiatric symptoms Diagnosis: Arylsulfatase A activity low in leukocytes Sulfatide excreation ↑ in urine Autosomal recessive different types of mutations in ARSA gene .

Adult-onset metacromatic leukodystrophy Woman, 25 yr Psychiatric symptoms for 6 years T2-w T2-w T1-w PD-w T1-w

= globoid cell leukodystrophy (GLD) Krabbe disease = globoid cell leukodystrophy (GLD) Many types: - congenital - early infantile - late infantile - juvenile - adult-onset Adult-onset type: spastic paraparesis, hemiparesis, ataxia, deteriorating vision Diagnosis: Galactocerebrosidase activity deficiency About 60 different mutations found in GALC gene

Adult-onset Krabbe disease Woman, 28 yr, 5-year history of spastic paraparesis T2-w FSE T2-w FLAIR

Adult-onset Krabbe disease Atrophic spinal cord T2-w FSE

Alexander disease Types: - infantile - juvenile - adult-onset Adult-onset type: diverse symptoms, episodic or progressive course Bulbar and pseudobulbar symptoms, spasticity, ataxia, dementia, nystagmus, palatal myoclonus GFAP mutation, Diagnosis = Genetic tests - Almost all cases sporadic - Autosomal dominant form exists

Adult-onset Alexander disease Woman 34 yr Ataxia, motor clumsiness, exaggerated reflexes, overactive bladder T2-w FLAIR

Adult-onset Alexander disease T2-w FSE Patchy contrast enhancement may occur

Adult-onset Alexander disease C II Pathologic white matter C IV Normal SI Atrophic spinal cord T2-w FSE

Adult onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms Age of clinical onset between 40-50 years of age Autonomic symptoms (bladder and bowel dysfunction, orthostatic hypotension) usually precede cerebellar and pyramidal symptoms Genetic basis: duplication of Lamin B1 with subsequent overexpression Diagnosis: - Clinical symptom constellation + MRI - Genetic analysis

Adult-onset ADLD with autonomic symptoms Asymptomatic family member Man, 37 yr

Adult-onset ADLD with autonomic symptoms 34-year-old asymptomatic family member

Adult-onset ADLD with autonomic symptoms Patient, 55 years

Adult-onset ADLD with autonomic symptoms Man, 57 years, with spasticity and ataxia Man, 51 years, wheel chair bound

Control Patients Woman, 59 years Woman, 49 years Man, 51 years T2 C 2

CADASIL = Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy Age at onset < 50 yr At least two of these symptoms: Stroke-like episodes with permanent neurologic signs Migraineous headache Major mood disturbances Subcortical dementia Diagnosis: Skin, muscle or brain biopsy Mutation in the NOTCH3 gene

CADASIL Woman 47 years T2-w FLAIR Douhan, Viola 19520105-1405 MRT 99-01-26 - Hereditet för CVS: Syster med multipla övergående CVS liknande episoder och mycket utbredd vitsubstansförändring vid CT och MRT. - Migränepisoder av komplex natur. Sommaren 1998 högersidig hemipares som väsentligen gått tillbaka. Leukoarios vid CT. - Nu vidareutredning. Dg: CADASIL (Cerebral autosomal dominant arteriopahy with subcortical infarcts and leukoangiopathy) T2-w FLAIR

Multiple cavernomas Familial form A 21-year-old woman, numbness in the right leg Her brother had had a bleeding in the spinal cord T2-w FSE T2*-w GRE T1-w SE contrast enhanced

Multiple cavernomas Familial form T2*-w GRE SWI sequence

Multiple cavernomas Familial form T2*-w GRE T1-w SE plain contrast enhanced T2-w FSE T2*-w GRE

Hereditary spastic paraparesis and thin corpus callosum (HSP-TCC) Autosomal recessive Genetically heterogenic In 35%, mutation in SPG 11 or SPG 15 gene SPG11 mutation: central retinal degeneration (Kjellin syndrome) Spastic paraparesis, cognitive decline, amyotrophy Symptom onset in 1st to 3rd decade Diagnosis: Clinical constellation + MRI + sequencing of candidate genes SPG 11 and SPG15

Hereditary spastic paraplegia and thin corpus callosum (HSP-TCC) The first MRI at age of 34 Female 46 yr.

Patient 2: 18 yr

atrophic and signal intensity changes Thorough and systematic analysis of atrophic and signal intensity changes Ruling out diseases with the same or similar symptoms Specific diagnosis Some alternative diagnoses

with clinicians and geneticists essential Thorough and systematic analysis of atrophic and signal intensity changes Ruling out diseases with the same or similar symptoms Specific diagnosis Some alternative diagnoses Collaboration with clinicians and geneticists essential