Other Mitochondria disease: MNGIE

MNGIE-  aut rec, presents with abdominal pain, malabsorption and weight loss.  Peripheral neuropathy and leukodystrophy occur.Serum lactate is almost invariably high.  Elevated thymidine is seen, and WBC shows decreased thymidine phosphorylase (buffy coat??).

Clinical presentations of mitochondrial cytopathies MELAS , MERRF and LHON

Melas- hypoacusis, ataxia, dementia, opthalmoplegia, encephalopathy, stroke like syndromes, exercise intolerance, proximal myopathy, type 2 diabetes.  Due to point mutation, can occur at most ages and mimic multiplle sclerosis with progressive or remitting and relapsing presentations

MERRF  isolated myoclonic epilepsy with or without ataxia, myopathy, peripheral neuropathy, and multiple lipomas in head region.  Neuropsychiatric manifestations including OCD, depression, psychosis and type two diabetes are common.  Any age of presentation to mid 40s.  Progressive decline

LHON-  painless, rapidly progressive vision loss with centrocecal scotoma in teenagers or young adults with male predominance (65-35).  Can mimic MS.

Mitchondrial cytopathies

visit http://www.mitomap.org/ for detailed information on cytopathies

Leigh disease (Complex 1>complex 2,3) aut rec
Succinate dehydrogenase gene (SDHB c and D) paraganglioma and pheochromocytoma, aut dom
polymerase gamma (POLG) mutations-- Alpers syndrome (hepatoencephalomyopathy), CPEO, spinocerebellar ataxia, sensory ataxia neuropathy with dysarthria and opthalmoplegia (SANDO),
ECGF1 (thymidine phosphorylase)- MNGIE

GI differential
liver involvement- Alpers syndrome
irritable bowel, intestinal pseudoobstruction--MELAS
severe GI dysfunction--MNGIE

Neuropathy-- MNGIE, SANDO

Historical points to ask about: deafness, short stature, early cardiac death in family, muscle discomfort or exercise intolerance, early onset DM.
Barth syndrome-- deafness and dystonia

Diagnostic tests
elevated lactate-- 60 percent sensitive, not completely specific
lactate/pyruvate ratio in CSF- may differentiate pyruvate dehydrogenase deficiency from primary mit. cytopathy
plasma amino acids-  elevated alanine may be seen
elevated CPK- may be seen in myopathy, not specific
alpha feto protein- may be seen in Alpers' syndrome early along with increased GGTPand others
thymidine levels-- high in MNGIE
urine organic acids-- high levels of ethylmalonic acid prompts ETHE1 gene for encephalopathy
     high 3 methyl glutaconic acid prompts look for tafazzin mutation for Barth syndrome
folate, B12, vitamin E- may be low in percentage coincidentally or secondarily

MRI- high T2 signal in putamen leading to striatal necrosis characterizes Leigh disease
occipital stroke-- consider MELAS

Cerebral palsy for adult neurologists: pearls

1.  Gross Motor Functional Classification System is most widely used

Level I  Ambulatory in all settings
Level II Walks without aids but has limitations in community settings
Level III Walks with aids
Level IV  Requires wheelchair or adult assistance
Level V  Fully dependent for mobility

Of all CP patients, 40 % are level I, and 66 % are levels 1-3 (ie. ambulatory)

2.  O CP patients, approximately one third will have spastic quadriplegia, one third spastic hemiplegia, one fifth spastic diplegia, and the rest either dyskinetic or ataxic-hypotonic CP.  It is rare for CP patients with spastic hemiplegia or spastic diplegia to be nonambulatory, but 75% of spastic quadriplegia patients are not ambulatory.  Those same patients are much more likely to suffer comorbidities such as epilepsy. 

3.  Genetic defects such as DCX and LISI can be sought, and coagulation pathway abnormalities (Leiden mutation eg.) among those suffering from placental thrombosis.

Care of hydrocephalus in adults pearls

1. Hydrocephalus may be decreasing.  Reasons may include higher threshold for surgery (artefact of practice) increased folate in pregnancy causing less myelomeningocoele.

2.  Unchanged CT scan does not exclude obstruction

3.  ETV or endoscopic third ventriculostomy is a more recent alternative to shunting in a highly select group of patients.  The procedure is more prone to immediate catastrophe, but less to long term infection, although obstruction can occur years later (as it can with any shunting procedure).  ETV may be best for older children with obstructive hydrocephalus or aqueductal stenosis.

4.  A top down approach to assessing meningocoele would sequentially assess hydrocephalus, Chiari malformation, syringobulbia.syringomyelia, tethered cord.

Diagnostic criteria for FXTAS (fragile x associated tremor ataxia syndrome)

Molecular-- CGG repeat 55-200
Clinical
   Major intention tremor, cerebellar ataxia
   Minor  Parkinsonism, moderate to severe short term memory loss, executive function deficit
Radiologic
   Major white matter lesions in middle cerebellar peduncles (MCP sign)
   Minor  lesions in cerebral white matter, moderate to severe brain atrophy

Diagnostic categories

Definite-- one major clinical, and one major radiologic, or present inclusions at autopsy
Probable-- two major clinical, or one minor clinical and one major radiologic
Possible-- one major clinical and one minor radiologic

Dystrophinopathies in adults: pearls

See also http://emgnotes.blogspot.com/2010/01/dystrophinopathy-clinical-diagnostic.html and here are ten more pearls

1.  Many DMD patients now live into 30s and 40s as do carriers or those with BMD.  DMD frequency is about 1:3500 whereas BMD is 1:15,000 to 1:35,000.

2.  Dystrophinopathy should be suspected in a child or adult with the following clinical signs/symptoms:  progressive skeletal muscle weakness, increased CPK, intellectual impairment, myalgias, or cardiomyopathy.

3. BMD patients by convention ambulate after 16.  In 40 + year olds, isolated quad weakness can be confused with IBM.  EKG findings are similar to DMD  (arrythmias or decreased EF requiring Ace inhibitors).  Chronic respiratory insufficiency can be associated with right heart failure.

4.  Minimally symptomatic BMD with exertional intolerance, myalgia, myoglobinuria, or elevated CK diagnostic yield increases with subtle signs such as clumsy as child, toe walking, positive family history, calf or tongue hypertrophy, or myopathic units on EMG. 

5.  All patients regardless of symptoms should have periodic pulmonary function testing, EKG, and echocardiography.

6.  Vaccinations including pneumococcal and influenza are recommended with low threshold for treating potential infections with antibiotics.

7.  Anesthetic risks mandate patients wear a med alert bracelet. These risks are minimized with nondepolarizing muscle relaxants. 

8.  Bowel program plus suction continuous via gj tube reduces abdominal pain.  Restricted jaw opening can mandate placement of a tube. 

9. Consider seated position or other creative safety measures during surgery if possible and if indicated.

10.  PT with range of motion and stretching exercises are hallmark.

Autosomal dominant ataxias with known causation

Most common types are SCA I,II, III, VI which comprise > 50 % cases in USA.  * indicates caused by polyglutamine CAG repeat expansion

SCA I--*-- begins as gait disorder, progresses to four extremity ataxia with dysarthria leaving patient wheelchair bound within 15-20 years.There is phenotypic variability and anticipation (genetically).  Clinically there is involvement of cerebellum with neuronal dropout of Purkinje cell layer and clinical involvement of the brainstem.  No supratentotial involvement.  Not as common as type II but well worked out molecularly,

SCA II--*--characterized by ataxia, dysarthria, slow saccades and neuropathy.  Originally Cuban description.  Very common worldwide, especially in India.  Slow saccades are not pathognomonic, they also are seen in SCA I and III.   Dementia, areflexia, myokymia also are seen. Gene expansion includes cytoplasmic protein ataxin, function of which is unknown.  Anticipation is marked, and disease may present in one generation in old age, in the next much earlier.  Number of repeats are 35-77 , with 32-34 "zone of reduced penetrance."

SCA III--*--Very common, is aka Machado-Joseph disease.  Presents with ataxia, eye movement abnormalities (bulging eyes, opthalmoparesis, staring eyes), speech and swallowing abnormalities.  Pathologic abnormalities include cerebellar afferent and efferents, pontine and dentate nuclei, substantia nigra, subthalamic, GP, cranial motor nuclei and anterior horn cells.  Ataxin 3 gene is at fault.  Repeats: normal 12-42, high is 52-84.  Early onset rigidity and dystonia (largest expansions), middle onset adult ataxia, late onset neuropathy (smallest expansions).  A few patients have Parkinson's that is dopamine responsive and even fewer have RLS.  Peripheral involvement is especially variable.  MRI shows range from fourth ventricle enlargement to severe olive sparing spino pontine cerebellar atrophy.

SCA-- V-- "Lincoln family ataxia"--slowly progressive dominant ataxia found in grandparents of Lincoln.  SPTBN2 gene ecoding B III spectrin is at fault. 

SCA VI  --*--  milder disease, pure cerebellar associated with normal lifespan.  Presentation is gaze evoked nystagmus, dysarthria, onset at age 50 or so, impaired vibratory and position sense.Its fairly common in Japan and in Germany.  Caused by expansion/repeat in voltage dependent calcium channel,same gene  that causes episodic ataxia type 2 and familial hemiplegic migraine.  However, mutations in these conditions in the same gene are different mutations.

SCA 7--*-- cerebellar brainstem disease associated with retinal degeneration and blindness.  It has striking instability of transmission especially with paternal transmission, with cases in utero and in childhood.

SCA 8--*-- classical presentation of disease with gait and limb ataxia, swallowing speech and eye movement abnormalities.  Most have progressive ataxia.

SCA 10 --*-- Mexicans with cerebellar symptoms and seizures.  Extremely large expansion is found in SCA 10 gene. Ashizawa.

SCA 11--*--  2 British families reported with benign gait and limb ataxia.  TTBK2 gene.

SCA 12 --*--PP2R2 gene with dominant ataxia presenting with upper extremity tremor, progressing to head tremor, bradykinesia, abnormal eye movements.  Onset 8-55 years.

SCA 13 --*-- dominant ataxia, may present in childhood with MR, dysarthria, nystagmus, +/- hyperreflexia.  Due to KCNC3 gene mutation in voltage gated K channel subunit.

SCA 14 --not repeat--slowly progressive ataxia with dysarthria in early adulthood.  May be pure cerebellar or accompanied by myokymia, hyperreflexia, axial myoclonus, dystonia and vibratory sense loss. 

SCA 15-16-- allelic (ie same allele) disorder occurring in Austrailian and Japanese families, slowly progressive pure cerebellar disorder.  Dysarthria, horizontal gaze evoked nystagmus, sometimes head tremor.  Disease is due to deletions in IPTR gene

SCA 17 --*--Widespread cerebral/cerebellar dysfunction, rare in US, more common in Japan.  Presents with gait and limb ataxia, psychiatric dysfunction, EPS, seizures, may resemble Huntington;s disease.  MRI shows widespread cerebral and cerebellar dysfunction.  Onset in mid to young adulthood.

SCA 26 -- Norwegian pure cerebellar ataxia that maps closely to gene affecting Cayman ataxia and SCA 6 with Purkinje cell degeneration. 

SCA 27-- Dutch disease manifests with hand tremor in childhood.

DRPLA-- *--  progressive ataxia, choreoathetosis, dementia, seizures, myoclonus, and dystonia. Before age 20 there are almost always seizures and a progressive myoclonic seizure like presentation.  Older patients get ataxia with choreoathetosis and dementia.  More common in Japan, but Haw River phenotype is an African American family in the Carolinas with seizures and cerebral calcifications.

episodic ataxias--EA1 and EA2 are due to mutations in K and Ca channel genes.  EA1-- patients ahve minutes of ataxia due to stress, exercise or change in posture. Patients also may have myokymia.   KCNA1 gene. EA2 has ataxia that lasts days , precipitated by stress, exercise or fatigue and is due to mutation of same gene as SCA 6 (CACNA1A4 gene). Acetozolamide may help.  Other EA's with prominent vertigo also are described.

Friedrich's ataxia, FARR, LOFA, VLOFA

Friedrich's ataxia (AR) is subclassified into classical (75%), FARR (FA with retained reflexes, adult onset), LOFA (late onset FA) and VLOFA (very late onset FA). 
In FA, pathology involves spinocerebellar tracts, lateral corticospinal tracts, posterior columns but NOT cerebellum.  Clinical features include a.  progressive gait ataxia and scoliosis  b.  gait worse in darkness (posterior column involvement)  and worsening during puberty    c.  dysarthria and hand incoordination   d.  areflexia  e. extensor plantars.  Associated features may include  e.  optic nerve atrophy (25%),  f.  SN hearing loss (10%)  g.  optic flutter or square wave jerks but not opthalmoplegia  h.  hypertrophic cardiomyoapthy (90%)  i. pes cavus  j. diabetes mellitus in 15 % 15 years after onset  j.  wheelchair bound after 15 years  k.  Death 30-70.
In FARR, LOFA, VLOFA, sporadic ataxia occurs without cardiomyopathy. Spasticity occurs, areflexia does not.  Again normal cerebellum.  Sporadic ataxia patients may warrant gene testing for frataxin.  Affected patients usually have 2 affected alleles, carriers have one.  Rarely, sequencing of second allele for FXN is needed to find a point mutation (compound heterozygosity).

Neurosarcoidosis pearls diagnosis

1.  Percent with cranial neuropathy-- 50-75 (most common VII, second II, all can be affected)

 

2.  Percent with parenchymal brain lesions-50

 

3.  Other manifestations - cognitive 20, meningeal 10-20, PN 15, seizures 5-10, spinal 5-10, myopathy 1.4-2.3

 

4.  Neuroendocrine presentations may include polydipsia, polyuria, panhypopituitarism, or massive obesity if sarcoid invades satiety center of hypothalamus

 

5.  Neuropathy can be virtually any type

 

6.  Myopathy can be acute, chronic or nodular and is usually subclinical. In contrast to steroid myopathy (the rule-out diagnosis often), sarcoid myopathy may have palpable nodules, contractures, cramps, elevated CPK, and fibrillation potentials and positive sharp waves on EMG.  Both steroid and sarcoid myopathy will have myopathic potentials.

 

7.  Contrast enhanced MRI to look for meningeal involvement is extremely important, but is not specific.

 

8.  Whole body PET imaging is better than Gallium and can be used to look for lymph nodes suitable for biopsy for diagnosis, but is not specific

 

9. CSF is normal in one third,but can show high protein, lymphocytosis, low glucose. OCB's , high IgG index

 

10.  CSF ACE levels are insensitive (24-55 %) but fairly specific (93%) for CNS sarcoid

 

11.  Heerfordt's syndrome consists of facial palsy, parotid enlargement, uveitis and fever and is considered so typical that tissue biopsy is not required