Spinocerebellar atrophies by mikesanye


									Spinocerebellar atrophies

Prof. Isidro Ferrer, Institut Neuropatologia, Servei Anatomia Patològica, IDIBELL-Hospital Universitari
de Bellvitge, Universitat de Barcelona, CIBERNED, Hospitalet de LLobregat; Spain
Classification of ataxias

1. Primary
1a. Sporadic SCAs
     Cerebellar cortical atrophy (CCA)
     Multiple system atrophy (MSA)
          Olivopontocerebellar atrophy (OPCA)
          Striatonigral degeneration (SND)
          Shy-Drager syndrome (SDS)
1b. Hereditary SCAs
     1b1.Autosomal dominant
     1b2. Autosomal recessive
     1b3. X-linked
          Fragile X tremor/ataxia syndrome (CGG trinucleotide repaet in the FMR1 gene at Xq27.3)
          Sideroblastic anaemia and spinocerebellar ataxia (ATP-binding cassette 7 transporter)
          X-linked cerebellar ataxia (Xp11.21-q21.3)
          Cerebellar ataxia with extrapyramidal involvement
          Art’s syndrtome, fatal X-linked ataxia with deafness and loss of vision (Xq21.33-q24)
2. Secondary
Multiple system atrophy (MSA), MSA-P: striato-nigral and MSA-C: OPCA

                                                                      Loss of Purkinje cells
                                                                      (A), axonal torpedoe
                                                                      (B), loss of neurons and
                                                                      gliosis in the inferior
                                                                      olive 8C) and dentate
                                                                      nucleus (D)

                                              Purkinje cell

                                 olivopontocerebellar atrophy: OPCA
OPCA. Pathology of Purkinje cells
as revealed with calbindin D 28 K
Multiple system atrophy (MSA), MSA-P: striato-nigral and MSA-C: OPCA

Loss of dopaminergic neurons in the substantia               Different types of intraneuronal cytoplasmic
nigra (A), oligodendroglial inclusions (B, C). Fibrilar      and intranuclear inclusions immunoreactive
ultrastructure of oligodendroglial inclusions (D)            with anti-ubiquitin antibodies.

                                            Inclusions are stained with anti-α-synuclein antibodies
α-synuclein in MSA abnormally interacts with Rab3a in cerebellum

                                                      α-synuclein immunoprecipitation in cerebellum

                                    IP syn
                 C       MSA   C     MSA
                                             +Prot G
 20 kDa

 IB anti-α-syn

                                    IP syn
                 C       MSA   C   MSA       Anti-α-syn
 29 kDa
                                             +Prot G

 24 kDa

 IB anti-rab3a

                     C   MSA   C    MSA      Anti-α-syn
                                             +Prot G

 55 kDa

 IB anti-α-tub
α-synuclein immunoprecipitation in cortex                                   IP syn
                                                         C       MSA    C   MSA
                                                                                       + protG

                                      20 KDa

                                      IB α-synuclein
                                                                             IP syn
                                                             C   MSA    C   MSA
                                                                                       + protG
                                      29 kDa

                                      24 kDa

                                            IB rab3a
rab3a immunoprecipitation in cortex
                                                                            IP rab3a
                                                             C    MSA   C     MSA
                                                                                       + protG
                                       29 kDa

                                       24 kDa

                                       IB rab3a

                                                                            IP Rab3a
                                                         C       MSA    C     MSA
                                                                                       + protG
α-synuclein in MSA abnormally           20 KDa
interacts with Rab3a in cerebral
cortex                                  IB α-synuclein

I. Non progressive recessively inherited ataxias
A. Hyper-reflexic
B. Hypo-reflexic

II. Intermittent ataxias

III. Progressive recessively inherited ataxias
A. Hyper or normo-reflexic
1. Early onset (Type I)
Type Ia
Type Ib
2. Childhood and adolescence onset (Type II)
Type IIa
Type IIb
3. Adult and late onset (Type III)
Type IIIa
Type IIIb
B. Hypo-reflexic
Early onset (Type IV)                              Friedreich’s ataxia. FRDA1 gene on chromosome
Type IVa                                           9q13-21.1
Type IVb
Type IVc
Type IVd
2. Childhood and adolescent onset (Type V)
Type Va
Type Vb
3. Adult and late onset (Type VI)
I. Non progressive recessively inherited ataxias

A. Hyper-reflexic
Congenital ataxic diplegia (Gustavson)
Congenital dysequilibrium syndrome (Sanner)
Non-progressive autosomal recessive ataxia, with mental retardation, optic atrophy and skin abnormalities
       (CAMNOS), Lebanese type

B. Hypo-reflexic
Congenital, non-progressive, cerebellar ataxia (Batten-Lamy, or “recessive infantile spastic diplegia”)
Recessive ataxia with ocular apraxia and hypoalbunemia, Portuguese type
Recessive ataxia with oculomotor apraxia and hypoalbuminemia, Japanese type

II. Intermittent ataxias

Hereditary hyperammonaemias associated with ataxia
           1. Congenital hyperammonaemia type II
           2. Citrullinemia
           3. Argeninosuccinic aciduria
           4. Hyperornithinaemia
Hyperalaninaemic and hyperpyruvate states
           1. Intermittent cerebellar ataxia
           2. Necrotising encephalopathy (Leigh´s disease)
Hartnup disease
Branched-chain ketonuria (Maple syrup urine disease)
III. Progressive recessively inherited ataxias

A. Hyper or normo-reflexic
1. Early onset (Type I)
Type Ia
•Ataxia-telentegiectasia (Louis-Bar syndrome) (ataxia telangiectasia mutated (ATM) gene 11q; 1-2 per 100,000)
•Amyotrophic familial spastic paraplegia
•Troyer syndrome
•Charlevoix-Saguenay syndrome
•Lesh-Nyhan syndrome
Type Ib
•Behr´s disease
•Sjögren-Larsson syndrome
•Congenital ataxia and aniridia (Gillespie Syndrome)
•Marinesco-Sjögren syndrome
•Progressive ophtalmoplegia, ataxia and neuropathy
•Ataxia, deafness and mental retardation (ADR synd)
2. Childhood and adolescence onset (Type II)
Type IIa
•Hereditary recessive spastic ataxia (R-SCD, or recessive spino-cerebellar) degeneration
•FARR, early onset with retained reflexes
Type IIb
•R-SCD with blindness and deafness (Hallgren´s syndrome)
•R-SCD and slow eye movements
•The Beauce R-SCD syndrome
•Ataxia, deafness, and oligophrenia syndrome (Jeune)
•Familial ataxia with peroneal muscular atrophy and optic atrophy
•Familial spino-cerebellar degeneration with cerebellar atrophy, neuropathy, increased serum creatine,
gamma globulins and alpha--fetoproteins
•Nephropthisis with progressive ataxia and retinal pigmentation
3. Adult and late onset (Type III)
Type IIIa
•Fickler-Wickler, recessive cerebellar atrophy of late onset
Type IIIb
•Spasic paraplegia, oligophrenia, amytrophy and retinal degeneration (Kjellin syndrome)
•Cerebellar ataxia and hypogonadism (Richards and Rundle syndrome)
•Familial cerebellar ataxia with hypergonadotropic hypogonadism and sensorineural deafness

B. Hypo-reflexic
Early onset (Type IV)

Type IVa
•Hereditary sensory neuropathy with ataxia
Type IVb
•HSN-Type E, with dysautonomia (Riley-Day syndrome)
Type IVc
•Cerebellar ataxia, motor neuron disease, learning difficulties, and dystonia
Type IVd
•Infantile onset spino-cerebellar degeneration with sensory neuropathy
   2. Childhood and adolescent onset (Type V)

   Type Va
   •FRDA1 classic type Friedreich’s ataxia (GAA triplet expansion in FRDA on chromosome 9q13; 1-2 per 100,000)
   •FRDA1 with rapid progression (Rimouski sub-type)
   •FRDA1 with very slow progression (Acadian sub-type)
   •FRDA1 with neurogenic muscle atrophy
   •FRDA1 early onset with retained reflexes
   •FRRR1 Friedreich´s ataxia with retained reflexes
   •FRDA1 presenting as pure sensory ataxia
   •FRDA1 presenting as spasic paraparesis
   •FRDA1 with generalised chorea
   •FRDA1-like phenotype with vitamin E deficiency (α-tocopherol transfer protein TTPA mutation; Ch. 8q13)
   •FRDA2 linked to 9p23-p11
   •Recessive HMSN (so-called “recessive Roussy-Levy Syndrome”)
   •Childhood ataxia with musculo-skeletal coenzyme Q10 deficiency

   Type Vb
   •Bassen-Kornzweig disease
   •Refsum´s heredopathia atactica polyneuritiformis
   •Polyneuropathy, oligophrenia, premature menopause, and acromicra (Lundberg´s Syndrome)
   •Unverrich-Lundborg disease, with myoclonic epilepsy and late onset ataxia

   3. Adult and late onset (Type VI)

   Gamma-glutamylcysteine synthetase deficiency
   LOFA, late onset Friedreich´s ataxia

CA= cerebellar atrophy; OPCA=olivopontocerebellar atrophy; PMCT=peripheral motor conduction time; CMCT=central motor conduction time; PNP=peripheral neuropathy.

Disease      Gene, gene-         Locus         Disease       Gene, gene    Locus
             product                                         product
SCA1         SCA1, ataxin 1      6p23          SCA15         ITPR1         3p26.1-p25.3
SCA2         SCA2, ataxin 2      12q24         SCA16
SCA3         MJD, ataxin 3       145q24.3-     SCA17         TATA box      6q27
                                 q31                         binding TBT
SCA4         puratrophin 1       16q22.1       SCA18         unknown       7q22-q32
SCA 5        βIII-spectrin       11p11-q11     SCA19/SCA22   unknown       1p21-q21
SCA 6        SCA6, CACNA1A       19p13         SCA20         unknown       11p13-q11
SCA 7        SCA7, ataxin 7      3p21.1-p12    SCA21         unknown       7p21.3-p15.1
SCA 8        SCA8                13p21         SCA23         unknown       20p13-p12.3
SCA 9        Not assigned        ..            SCA25         unknown       2p21-p13
SCA 10       SCA 10, ataxin 10   22q13         SCA26         unknown       19p13.3
SCA 11       TTBK2               15q14-q21.3   SCA27         FGF-14        13q34
SCA 12       PP2R2B              5q31-q33      SCA28         AFG3L2        18p11.22-q11.2
SCA 13       KCNC3               19q13.3-      SCA30
SCA14        PRKC gamma          19q3.4        SCA31         BEAN-TK2

                           Gene       Mutation        Effects

Polyglutamine expansions

SCA1                       ATXN1      CAG repeat      Toxic accumulation of aggregates
SCA2                       ATXN2      CAG repeat      Toxic accumulation of aggregates, altered calcium homeostasis,
                                                      mitochondrial dysfunction
SCA3                       ATXN3      CAG repeat      Toxic accumulation of aggregates, altered transcription
SCA6                       CACNA1A    CAG repeat      Altere calcium homeostasis, mitochondrial dysfunction
SCA7                       ATXN7      CAG repeat      Toxic acumulation of aggregates, abnormal chromatin structure, altered
                                                      transcription, mitochondrial dysfunction
SCA17                      TBP        CAG repeat      Toxic accumulation of aggregates, altered transcription
DRPLA                      ATN1       CAG repeat      Toxic accumulation of aggregates, altered transcription, mitochondrial
Non-coding expansions

SCA8                       ATXN8      CTG repeat      Toxic accumulation of aggregates
SCA10                      ATXN10     ATTCT           Abnormal chromatin structure
SCA12                      PPP2R2B    CAG repeat      Abnormal neuronal protein phosphatase activity, mitochondrial dysregulation
SCA31                      BEAN-TK2   TGGGAA repeat
                         Gene     Mutation               Effects

Convencional mutations

SCA5                     STBN2    Missense, deletion     Altered axonal transport due to altered βIII-spectrin
SCA11                    TTBK2    Framesdhift            Tau phosphorylation
SCA13                    KCNC3    Missense               Potassium-channel dysfunction (Kv3.3)
SCA14                    PRKCG    Missense               Altered protein kinase Cγ
SCA15/16                 ITPR1    Missense, deletion

SCA20                             Duplication

SCA27                    FGF14    Missense, frameshift

SCA28                    AFG3L2   Missense               Abnormal mitochondrial function
Main clinical symptoms of SCAs

Disease        Mean age at            Characteristic signs                                                    CT or MRI
name           onset in years                                                                                 findings

SCA1           37 (4-74)              Ataxia, dysarthria, nystagmus, slow saccades,
                                      ophthalmoplegia, spasticity, PNP, executive dysfunction                 OPCA
                                      increase in PMCT and CMCT
SCA2           32 (1-65)              Ataxia, dysarthria, slow saccades, hyporeflexia,                        OPCA + spinal
                                      titubation, dementia, (rarely) parkinsonism                             atrophy; some
                                                                                                              cortical atrophy
SCA3           36 (5-70)              Ataxia, dysarthria, nystagmus, lid retraction, diplopia,                OPCA (mild), 4th
                                      faciolingual, fasciculation, dystonia, parkinsonism,                    ventricle enlarged
                                      restless legs, temperature discrimination; onset <35
                                      years with ataxia + spasticity, onset >45 years with
                                      ataxia + PNP
SCA4           ? (19-72)              Ataxia, dysarthria,          sensory       axonal     neuropathy,       CA
                                      pyramidal signs

SCA5           30 (10-68)             “Pure” ataxia, dysarthria, normal life expectancy; early                CA
                                      onset, bulbar signs

SCA6           52 (30-71)             “Pure” ataxia, dysarthria, nystagmus, normal life                       CA
                                      expectancy, (commonly) diplopia, (rare and mild) PNP,
                                      pyramidal signs, negative family history owing to late

CA= cerebellar atrophy; OPCA=olivopontocerebellar atrophy; PMCT=peripheral motor conduction time; CMCT=central motor conduction time;
PNP=peripheral neuropathy.
Main clinical symptoms of SCAs

Disease        Mean age at              Characteristic signs                                                       CT or MRI
name           onset in years                                                                                      findings

SCA7           35 (0-70)                Ataxia, dysarthria, visual loss owing to pigmentary
                                        retinopathy, slow saccades, pyramidal signs                                OPCA
SCA8           40 (1-73)                Ataxia, dysarthria, nystagmus, tremor                                      CA

SCA10          36 (26-45)               Ataxia, dysarthria, nystagmus, epilepsy                                    CA

SCA11          25 (15-43)               “Pure” ataxia, dysarthria, nystagmus                    normal      life   CA
                                        expectancy, (rarely) hyperreflexia

SCA12          35 (8-55)                Ataxia, nystagmus, tremor, bradykinesia, hyperreflexia                     CA + cerebral

SCA13          Childhood (<1-45)        Ataxia, dysarthria, nystagmus, hyperreflexia, mental and                   OPCA
                                        motor retardation, slow progression

SCA14          27 (12-42)               Ataxia (slow progression) ± head tremor or myoclonus                       CA (vermis)
                                        (early onset)

SCA15          26 (10-50)               “Pure” ataxia, dysarthria, nystagmus, normal                        life   CA (vermis)
                                        expectancy; some patients with hyperreflexia

CA= cerebellar atrophy; OPCA=olivopontocerebellar atrophy; PMCT=peripheral motor conduction time; CMCT=central motor conduction time;
PNP=peripheral neuropathy.
Disease   Mean age at      Characteristic signs                                       CT or MRI findings
name      onset in years
SCA16     40 (20-66)       “Pure” ataxia, dysarthria, nystagmus, normal life          CA
                           expectancy; some patients with head tremor
SCA17     33 (6-48)        Ataxia, dysarthria, nystagmus, with dementia, slow         CA, some: general
                           saccades or epilepsy,hyperreflexia, akinexia,              atrophy
                           dystonia, chorea, psychosis, mutism
SCA18     15 (12-25)       Ataxia, dysarthria, nystagmus,          sensory-motor      CA
                           axonal neuropathy, Babinski sign
SCA19     34 (11-45)       Mild ataxia, dysarthria, nystagmus,           cognitive    CA, some: cerebral
                           impairment, myoclonus, tremor                              atrophy
SCA20     Variable,        Dystonia and dentate calcification,         dysarthria,    CA, calcification dentate
          anticipation     ataxia, palatal myoclonus                                  nuclei
SCA21     18 (7-30)        Ataxia, dysarthria,akinesia, rigidity, postural and rest   CA
                           tremor, hyporeflexia, cognitive impairment
SCA22     ? (10-46)        Ataxia, dysarthria, nystagmus, slow progression,           CA
SCA23     Late-onset       Ataxia, distaría, hyperreflexia, loss of vibratory         CA
SCA25     ? (1-39)         Ataxia, dysarthria, nystagmus, sensory neuropathy          CA
SCA26     26-60            Ataxia, abnormal pursuit                                   CA
SCA27     34 (27-40)       Ataxia, dysarthria, nystagmus, tremor, psychiatric         CA
SCA28     12-36            Ataxia, nystagmus, ophtalmoparesis, ptosis                 CA
Clinical orientation

Clinical sign          First line investigations   Second line investigations

Pure cerebellar        SCA6, SCA5                  SCA11, SCA14, SCA15,
ataxia                                             SCA16, SCA22
Dementia               SCA17, DRPLA                SCA2, SCA13, SCA19, SCA21
Psychosis              DRPLA, SCA17                SCA3, FGF14 (episodes)
Epilepsy               SCA10, DRPLA                SCA17
Chorea                 DRPLA, SCA17                SCA1 (late stage)
Myoclonus              DRPLA                       SCA2, SCA19
Tremor                 SCA2, SCA8, SCA12           SCA16, SCA21, FGF14
Parkinsonism           SCA3, SCA12                 SCA2, SCA21
Dystonia               SCA3                        SCA17
Spasticity             SCA3                        SCA1, SCA7
Peripheral             SCA3, SCA4, SCA18, SCA25    SCA1
Ophthalmoplegia        SCA3, SCA2, SCA1
Slow saccades          SCA2                        SCA7, SCA1, SCA3, SCA17
Pigment retinopathy    SCA7
Hearing loss, ataxia   SCA31

Gene located on chromosome 6p23, gene product: ataxin 1, a nuclear protein of unknown function.

Clinical features: variable and depending on the size of the CAG repeat expansion.
Onset: from childhood to late adult life, mean fourth decade.
Dysarthria, truncal and limb ataxia followed by reduction or absence of saccadic eye movements, gaze
paresis, spasticity, peripheral neuropathy and mild cognitive impairment.

Neuropathology: Pattern of olivopontocerebellar atrophy with loss of Purkinje cells and dentate
neurons, atrophy of the pons and marked loss of olivary neurons. Red nuclei, nuclei of nerves III, X and
XII, and anterior horns affected. Substantia nigra usually spared. Moderate involvement of the pallidum,
striatum and cerebral cortex.
Involvement of the posterior columns and spinocerebellar tracts.
Intranuclear inclusions immunoreactive for ataxin 1 in many areas but not in Purkinje cells.
Clinical findings

Complete clinical data were obtained in 22 patients.
Ataxia, dysarthria, titubation, dysdiadochokinesia and dysmetria occurred in all cases.
Pyramidal signs in ten, dementia in eight and ocular motor disturbances (absence of optokinetic
nystagmus, upward gaze palsy and lid retraction) in nine.
Cognitive dysfunction was present in two clinical forms: i. frontal-like syndrome with euphoria
and emotional lability; and ii. Noctural shouting and crying, irritability and aggressiveness.
Dysphagia occurred in most cases; amyotrophy was common, and respiratory failure appeared
with disease progression.
Chorea, torticollis, tongue atrophy, fasciculations, sphincter dysfunction, and deep sensation
loss were less frequent findings.
                                                                  Mean CAG repeats in relation to sex, generation and
                                                                  parental sex

The at-risk unaffected group is at left (shaded). The affected group is at right (white).
Age is the age for the at-risk unaffected; age of onset is the age of the first detected symptom for the affected group.

                                                       Age at onset of early signs and symptoms and CAG-repeat
                                                       number in pre-symptomatic analysis of SCA1

Gene located on chromosome 12q24.1 encoding for the protein ataxin 2.

Clinical features: Age of onset, variable from infancy to adult life. Anticipation. Infantile onset in cases with
very long repeats.
Ataxia, tremor, slow saccadic eye movements, hyporeflexia, sensory neuropathy, myoclonus.
Parkinsonism, cognitive impairment, amyotrophy, chorea and oculomotor paresis in some cases.

Neuropathology: Pattern of olivopontocerebellar atrophy with depletion of Purkinje cells but relative
preservation of dentate nucleus.
Neuron loss in the substantia nigra pars compacta, pallidum and neostriatum.
Involvement of the Clarke’s column, spinocerebellar tracts and dorsal columns, but not of the corticospinal
Cytoplasmic and intranuclear inclusions immunoreactive for ataxin 2 in many areas but not as frequent as
in other SCAs.
Spinocerebellar ataxia-2 (SCA-2): SCA2, ataxin 2, 12q23-24.1

                                              Cerebellar atrophy, mainly involving the vermis, atrophy
                                              of the pons and olivary nuclei, degeneration of the dorsal
                                              columns and spinocerebellar tracts of the spinal cord
                                                                Intranuclear neuronal inclusions: INI; ubiquitin

Loss of dendritic spines, reduced dendritic arbors and axonal torpedoes in Purkinje cells. Golgi method

Additional pathological findings:

Loss of neurons in the substantia nigra
Loss of motorneurons and neurons in the Clarke’s column
Axonal degeneration in the peripheral nerves
INI, ubiquitin and ataxin 2 in SCA2
Double-labelling immunofluorescence with anti-ubiquitin (A, green) and anti-synuclein (B, red), showing co-localization (C,
yellow) in intranuclear nuclear inclusions
Neurosci Lett 381 (2005) 247-251


            22/22          22/22           22/22   22/36           22/22           -/-   22/22
                                                   1                               2

                                   22/23                   22/22
Patient 1

Dysarthria and difficulties in walking at the age of 27 years coincidental with the pregnancy of a
single girl.
Neurological deficits progressed slowly during the following 10 years with bruxism, screaming
episodes and agitation.

MRI studies at the age of 42 showed vermian and hemispheric cerebellar atrophy, pontine atrophy
and severe cerebral leucoencephalopathy.

The patient evolved rapidly with tretraparesia in flexion, myoclonic jerks, urinary and faecal
incontinence, and mental deterioration and dementia.

She died at the age of 46.

Genetic studies: DNA obtained from the paraffin blocks.
SCA2: 22 CAG triplets in the normal allele and asequence of 36 CAG triplets in the mutated alleles.
No abnormalities in SCA1, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17 and DRPLA.
Patient 2

A younger sister with diabetes mellitus, diagnosed at the age of 25 years, started with difficulties in
walking, dysarthria and bruxism at the age of 31.

The disease progressed rapidly with practical impossibility of walking 5 years later, together with
mental impairment, anosognosia, hypersexuality, aggressiveness, choreoathetosis and severe
language deterioration.
MRN studies disclosed vermian and hemispheric cerebellar atrophy and bilateral hyperintensities in
the subcortical white matter
She died at the age of 40.

Genetic study: available material not suitable for DNA study.
Loss of Purkinje cells (A); axonal torpedoes (arrow)
recognized with antibodies against phosphorylated
neurofilament epitopes (B); loss of neurons in the inferior
olkivary    nucleus      (C);    Ubiquitin-immunoreactive
intranuclear inclusions (arrow) in a pontine neuron (D).
     A                                                       B


                                                              D                      cc                           cso

Marked demyelination of the centrum semiovale (A and B) at the level of the caudate/putamen () and thalamus (B).
Atrophy of the cerebellum with myelin pallor in the vicinity of the dentate nucleus (C). Preservation of fibers in the corpus
callosum (cc) compared with the centrum semiovale (cso) (D)
SCA3: Machado-Joseph disease

Gene on the chromosome 14q32.1 encoding for ataxin 3.
Anticipation linked to paternal transmission.

Clinical features:
Type 1: onset from 5 to 30 years.
Mild ataxia, but marked spasticity, rigidity and bradykinesia. Bulging of the eyes prominent in some
Type 2: onset by the fourth decade.
Gait ataxia, dysarthria, espasticity, nystagmus, supranuclear ophthalmoplegia, bulbar and limb
amyotrophy, loss of reflexes.
Type 3: onset by the fifth decade.
Ataxia, sensorimotor neuropathy, amyotrophy and areflexia.
Type 4: similar to type 3 plus parkinsonism.

Cerebellar cortex and olivary nuclei largely spared.
Neuronal loss in Clarke’s column, vestibular nuclei, dentate nucleus, pontine nuclei and red nuclei.
Loss of neurons in the substantia nigra, subthalamic nuclei and, lesser, in the pallidum.
Loss of motorneurons in the bulbar nuclei and anterior spinal horn. Degeneration of the
spinocerebellar tracts and posterior columns.

Intranucler neuronal inclusions that contain ubiquitin and ataxin 3.
Machado-Joseph disease in a family of Spanish origin
Pou-Serradell A, Russi A, Ferrer I, Galofre E, Escudero D
Rev Neurol (Paris) 1987; 143:520-525

22 members affected (15 men, 7 women) over six generations. Age at onset between 38 and 73
Main clinical symptoms:
ataxia, akinesia, distal amyotrophy, progressive external ophthalmoplegia, facial and lingual
fasciculations, loss of sensibility in the lower extremities and bulging eyes. Pyramidal signs in some
cases, frontal signs in a few cases.

Neuropathological examination in one case:
•neuron loss in the pons, with relative preservation of the inferior olives and cerebellar cortex
•neuron loss in the substantia nigra
•degeneration of the dorsal, spinothalamic and spinocerebellar tracts in the spinal cord, marked nerve
cell loss in the Clarke’s column
•marked loss motor neurons of the anterior horn and nuclei of the III, IV and VII cranial nerves
•axonal degeneration of the peripheral nerve
•intranuclear neuronal inclusions
                                                        NII: ubiquitin

                                        cerebellum: relative preservation of
                                        the cerebellar cortex

                                      spinal cord: degeneration of dorsal
                                      columns and spinocerebellar tracts

                                        peripheral nerve: axonal degeneration
Midbrain: atrophy of the pons,
preservation of the inferior olives

 Skein-like inclusions in motorneurons of the spinal cord
Patient 1
First symptoms at the age of 50 years, slowly progressive gait ataxia and dysarthria.
At the age of 78, the patient was oriented, her speech was dysarthric and the ocular motility
showed slow pursuit and paresis of the superior vertical gaze; amyotrophy of the extremities,
hyporeflexia and Babinski sign; reduced distal sensitivity in both legs; impaired coordination of
the extremities and marked gait ataxia.
Loss of memory appeared at the age of 82 rapidly followed by severe cognitive impairment.
She died at the age of 86 years.
Genetic study: mean number of CAG repeats in SCA3 was 27/70.

Patient 2
First symptoms at the age 32 characterized by progressive gait instability, dysphagia to
liquids, diplopia and weakness on her legs.
The neurological examination at the age of 36 revealed, in addition, disclosed dysarthria,
nystagmus to the bilateral gaze, ptosis, hyperreflexia and decreased superficial distal
sensitivity in the legs.
At the age of 48 she had severe dysarthria, paresis of the vertical and horizontal gaze, rigidity
and bradykinesia of the extremities, generalised amyotrophy, loss of tendon reflexes and
denervation of the paraspinal muscles.
She died at the age of 49 years.
Genetic study: mean number of CAG repeats in SCA3 was 21/74
Cranial T1-weighted MR sequence in the sagital plane showing atrophy of the
cerebellum, pons, medulla oblongata and spinal cord (patient 1)
Neuropathological study

Mild cerebral atrophy, marked cerebellar atrophy, particularly in the vermis, and pons.
Marked loss of Purkinje cells and granule cells, and axonal torpedoes. Loss of neurons in the dentate
nuclei, inferior olives and pons.
Neuron loss in the anterior horn of the spinal cord, motor nuclei of the medulla oblongata, facial
nucleus and oculomotor nuclei, more marked in patient 2.
Moderate neuron loss in the substantia nigra and locus ceruleus.
Loss of axons and myelin in the anterior roots and nerves of the spinal cord, and dorsal columns,
dorsal spinothalamic and spinocerebellar tracts. Myelin pallor of the pyramidal tract in patient 1.
Loss of neurons in the superior colliculus.
NIIs in neurons of the anterior horn, nuclei of the medulla oblongata and pons, but not in the
cerebellum, substantia nigra and locus ceruleus.

(+ AD stage V of Braak and LBD stage 5 of Braak in patient 1)

Cerebellar atrophy, particularly in the vermis

Myelin pallor in dorsal columns, dorsal spinothalamic and
spinocerebellar tracts (patient 2)

                                                              Neuronal loss in the anterior horn of the spinal
                                                              cord (A), motor nuclei of the vagus nerve (B) and
                                                              substantia nigra (C). An axonal torpedo (asterisk)
                 Neuronal intranuclear inclusion. Ubiquitin   is observed in the vermis (D)
Although NIIs correlate with neuron loss in the pons, medulla    Mosaicism of the expanded allele in
oblongata and anterior horn of the spinal cord, there is no      several brain regions. Although in this
correlation in other brain regions, including the midbrain and   PCR the caudate and putamen did not
cerebellum, in which neuron loss is not accompanied by the
presence of NIIs.
                                                                 show amplification, they did in the other
                                                                 two PCR studies. Very low degree of
                                                                 mosaicism between regions without
                                                                 neuronal loss and regions with marked
                                                                 neuronal loss points to existence of
                                                                 selective cellular vulnerablity to the
                                                                 genetic defect
Dentatorubropallidoluysian atrophy (DRPLA)
Gene on chromosome 12p13.31 encoding for the protein atrophin 1; DRPL is caused by an expansion
of CAG repeat in atrophin 1

Clinical features: Age of onsetb variable depending on the extent of repeats
Onset in childhood: myoclonic epilepsy, ataxia, cognitive decline
Onset in young adults (20 years): ataxia, chorea and dementia; seizures rare of absent
Onset in adults: olivopontocerebellar atrophy, chorea

Neuropathology: Atrophy of the globus pallidus (pars externa) and subthalamus; neuron loss in the
dentate nucleus with grumose degeenration of remaining neurons; gliosis of the red nucleus.
Mild involvement of the pons, inferior olives, substantia nigra, neostriatum and thalamus.
Axonal loss in the posterior columns and spinocerebellar tracts

Cases with the Haw- River variant (African American kindred) may have microcalcification in the
globus pallidus, neuroaxonal dystrophy in the nucleus gracillis and demyelination of the cerebellar
white matter
Intranuclear and intracytoplasmic inclusions containing ubiquitin and atrophin 1, and particularly,
diffuse staining with antibodies against expanded glutamine tracts, in several areas.
Beginning at the age of 27 years with behavioral changes, irritability, depression and gait instability.
At the age of 50 she was unable to continue to work because of frequent falls, and she required
assistance in walking; slurred speech, memory disturbances, and she had become untidy.
At the age of 62 years developed sphincteral incontinence, insomnia and psychomotor agitation.
Occasional slight choreic movements, of the head; upper- and lower-limb dysmetria and
dysdiadochokinesia. Standing up and gait, impossible. Subcortical cognitive impairment with anterograde
memory loss and slowing of verbal responses.
Bruxism was added at the age of 63.
She died at the age of 67 years.

                                                              A-C: images at 62 years; D-F: images at 67 years
General neuropathological findings: neuronal loss and astrogliosis in the dentate nuclei, subthalamus and outer globus
pallidus. Mild neuronal loss in tectum and tegmentum, olivary nuclei, red nuclei and substantia nigra. Rare skein-like
inclusions in the dorsal nuclei of the medulla oblongata.

                                                                 Severe white matter involvement.        Intranuclear
                                                                 ubiquitin-immunoreactive inclusion in   the lateral
                                                                 reticular formation of the brainstem

Genetic study: 2 alleles of 15/60CAG repeats in the B37 gene

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