1 A whirlwind tour of eponyms and other hard-to-remember minutiaePEDIATRIC GRAY MATTER DISEASES Degenerative neurological diseases presenting in the 1st six years of life A whirlwind tour of eponyms and other hard-to-remember minutiae Steven Leber, M.D., Ph.D. January 12, 2017

2 Normal Delayed Developmental level Regression Age

3 HOW DO WE CLASSIFY NEUROMETABOLIC DISORDERS?Disorders of lipid metabolism Disorders of carbohydrate metabolism Disorders of urea cycle enzymes Disorders of amino acid metabolism Disorders of organic acids Mucopolysaccharidoses Mucolipidoses Disorders of trace metal metabolism Disorders of purine & pyrimidine metabolism Mitochondrial disorders Peroxisomal disorders

4 “GRAY MATTER” vs “WHITE MATTER”Early seizures Common Uncommon EEG Sharp Slow Dementia Early Variable Motor deficit Variable early; later severe Prominent early Visual deficit Early; usually retinal; abnormal ERG Later; optic nerve or usually tract; abnormal VER

5 CLASSIFICATION Infantile vs late infantile With or without visceral storage

6 INFANTILE, WITHOUT VISCERAL STORAGETay-Sachs Alper Menke Rett Farber Pompe Leigh Infantile neuroaxonal dystrophy "Cerebral" GM1 gangliosidosis (type II) Infantile neuronal ceroid lipofuscinosis (NCL, CLF) Congenital disorder of glycosylation type Ia Not covering italicized

7 INFANTILE, WITH VISCERAL STORAGEGeneralized GM1 gangliosidosis Gaucher's (infantile) Niemann Pick, type A Sandhoff Wolman Glycolipid and glycoprotein disorders(fucosidosis, mannosidosis, sialidosis, I-cell disease)

8 LATE INFANTILE, WITHOUT VISCERAL STORAGENeuronal ceroid lipofuscinosis Juvenile Tay-Sachs Progressive myoclonus epilepsies Huntington disease Xeroderma pigmentosa

9 LATE INFANTILE, WITH VISCERAL STORAGEGaucher Type III Niemann Pick, type C Mucopolysaccharidoses Hurler's Hunter's Sanfilippo's

10 INFANTILE, WITHOUT VISCERAL STORAGETay-Sachs Alper Menke Rett Farber Pompe Leigh Infantile neuroaxonal dystrophy "Cerebral" GM1 gangliosidosis (type II) Infantile neuronal ceroid lipofuscinosis (NCL, CLF) Congenital disorder of glycosylation type Ia

11 TAY-SACHS DISEASE (GM2 GANGLIOSIDOSIS)Onset: 0-6 months, usually 1-3 Early myoclonus (startle, without habituation, especially to noise [hyperacusis]) and irritability Seizures in first six months (infantile spasms, gelastic or other partial, generalized). Dementing Hypotonic at first; progressively weak; later spastic Macrocephaly usually begins at ~ 18 months (brain weight often > 2000 gm) Progressive; most die in 2nd or 3rd year Milder forms exist Highlighting with italics

13 TAY-SACHS DISEASE - GeneticsNot only Ashkenazi Jews Carrier frequency Ashkenazi Jews: 1 in 30 Those from small area near Lithuania: 1 in 19 Prior to screening, 1 in Ashkenazi Jews were affected; screening has ↓’d by >90% Non-Jews 1 in 300 Pockets of higher incidence Western China French Quebec Pennsylvania Dutch Louisiana Cajun

14 Ceramide

15 N-acetylneuraminic acid = sialic acid

16 GANGLIOSIDE NOMENCLATUREG: ganglioside M: how many sialic acids A 0, M 1, D2, T3 Number: position on band Smaller (few hexoses) migrate faster; have higher numbers 4 sugars: 1 (e.g., GM1) 3 sugars: 2 2 sugars: 3

17 Comment that there is only one know synthetic mutation: GM3 synthase deficiency, affecting Amish, with infantile onset epilepsy, developmental stagnation, and blindness

18 TAY-SACHS DISEASE Hexosamindase A = α β Hexosamindase B = β2Tay-Sachs: α-subunit mutation Chromosome 15 Hexosaminidase A deficiency Cannot breakdown GM2 ganglioside Accumulates in lysosomes Sandhoff's: β-subunit mutation Hexosaminidase A & B Like Tay-Sachs but with visceromegaly Rarer than Tay-Sachs Death usually by age 4

19 TAY-SACHS DISEASE - PathologyBallooned cells with swollen axons (torpedoes) and membranous cytoplasmic bodies If survive long enough, often cystic white matter changes

20 ALPER (progressive infantile poliodystrophy)Controversial and difficult to define Triad of progressive: Refractory epilepsy Dementia Liver failure Familial in some Onset in neonatal period to 1st few years Arrested head growth  microcephaly Vegetative after 1-3 years

21 ALPER Severe cortical neuronal degeneration (especially layers III and IV) No visceral or brain storage Liver cirrhosis in some Pathologic diagnosis, plus one of exclusion and family hx Can be caused by mutation in the nuclear gene encoding mitochondrial DNA polymerase gamma (POLG), leading to mitochondrial DNA depletion Risk of valproate-induced hepatic failure!

22 MENKE X-linked recessive Onset: 1st weeks to monthsXq13 Onset: 1st weeks to months Prominent seizures and myoclonus at onset Severe dementia and regression Hypotonic with brisk DTRs Hypothermia, hypoglycemia, and prematurity common

24 MENKE Copper and ceruloplasmin both lowin brain and liver (high in intestine, kidney, and fibroblasts) Intestinal malabsorption Cu++ and ceruloplasmin may be nl 1st few weeks of life Menkes gene (MNK) product copper-transporting ATPase Copper-dependent enzymes (e.g., cytochrome-c-oxidase, dopamine ß-hydoxylase) malfunction Parenteral copper injections help survival and neurologic symptoms in pts with certain mutations if treatment started in the neonatal period Update

25 MENKE Vasculopathy; tortuous cerebral vessels Pathological fx’sPathology Diffuse atrophy plus focal infarctions Subacute inflammatory meningoencephalitis Hemorrhages common (ddx – abuse) Pathological fractures

26 RETT SYNDROME Almost exclusively girlsCommon; one of most common genetic causes of mental retardation in girls Incidence in US: up to 1 in 10,000 female births

27 RETT SYNDROME: 4 clinical stagesNormal at birth I. At 6-18 months: Developmental arrest Development slows and then arrests Possible decrease in eye contact and communication Diminished interest in play Head growth decelerates Acquired microcephaly Seizures not common but can occur

28 RETT SYNDROME: 4 clinical stagesII. 1-4 years (usually 2nd year): rapid regression Phase lasts days to months Dramatic deterioration; can appear encephalitic or toxic Loss of language skills Autistic behavior Decreased purposeful use of hands Stereotyped hand-wringing, slapping, or hand-to mouth movements

29 RETT SYNDROME: 4 clinical stagesStage II, continued: Ataxia of trunk and extremities Gait apraxia Seizures (GTC, complex partial, atypical absence) Apnea, then hyperventilation, only during wakefulness Episodes of jerky movements Insomnia and sleep disturbance Self-abusive behavior Bruxism, aerophagia GI problems (constipation, GER, poor growth)

30 RETT SYNDROME: 4 clinical stagesIII years of age: pseudostationary Lasts months to years Apparent stabilization Autistic behavior less prominent, improved personality, eye contact Increased rigidity, bruxism Continued seizures and gait ataxia/apraxia Continued sleep problems Poor weight gain Prolonged QT

31 RETT SYNDROME: 4 clinical stagesIV. Teenage years: late motor deterioration Slow deterioration Ambulation lost Spasticity plus LMN signs Dystonia, parkinsonian features may occur Scoliosis, foot deformities Reduced seizure frequency Improved eye contact Most survive to 5th or 6th decade

32 RETT SYNDROME - EtiologyPathology: Moderate neuronal loss and cortical/dendritic atrophy Despite developmental regression, not felt to be degenerative Gene MeCP2 identified in 1999 Methyl-CpG binding protein-2 Affects regulation of other genes (“expression silencer”) MeCP2 protein binds to methylated DNA, activating histone deacetylase Mutations allow gene to be inappropriately turned on Testing is now 96% sensitive (CDKL5, FOXG1 in ddx) In mice, about 2200 genes downregulated and 300 upregulated

33 RETT SYNDROME - GeneticsPhenotypic severity correlates with proportion nl vs mutant X-chromosome inactivated Spontaneous mutations 99%, familial 1% Spontaneous mutations almost always occur in sperm Boys: familial cases or in-ova mutations

34 RETT SYNDROME- VariantsFemales Classic Preserved speech variant (Zappella variant) Early seizure variant (Hanefeld variant) Mental retardation and seizures Pure autism Angelman-like Mild mental retardation Boys Severe neonatal encephalopathy; usually die in 1st year Mild MR, seizure, ataxia Bipolar or schizophrenic Whom to test???? Tremor seems to be prominent in most

36 FARBER LIPOGRANULOMATOSISHypotonia Usually dementing, but some normal No seizures ↓ acid ceramidase   ceramide with anterior horn cell storage May have cherry-red spots

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38 POMPE DISEASE (glycogen storage type II disease; acid maltase deficiency)Onset at several weeks to several months of age Involves brain and muscle Presents with profound hypotonia & weakness, little spontaneous movement (resembles SMA) Later develop dementia

40 POMPE DISEASE Treatment with alglucosidase alfa approved by FDA in 2006 Early treatment (compared to an untreated historical control group) Reduced the risk of death by 99% Reduced the risk of death or any type of ventilation by 88% Significantly improved motor and cognitive development Basis of movie Extraordinary Measures Cost: $60-400,000 per year

41 LEIGH SYNDROME (subacute necrotizing encephalomyelopathy)Onset in early infancy (60% in 1st year) or childhood; rarely in adulthood Neonatal form Acidosis Severe retardation Usually early death Other types with variable clinical picture: Steadily progressive, saltatory, or episodic May progress with intercurrent infections Typically associated with lactic acidosis

42 LEIGH – Symptoms and signsRetarded motor and intellectual development Respiratory disturbances Ophthalmoplegia Dysphagia and weight loss Vomiting Hypotonia & weakness Ataxia

43 LEIGH – Symptoms and signsSeizures Visual loss Nystagmus Dystonia Peripheral neuropathy (often subclinical) Fevers

44 LEIGH - Pathology Brainstem and basal ganglia lesions commonNecrosis around 4th ventricle and aqueduct. Distribution resembles Wernicke's without mammilary bodies and without hemorrhage

45 Figure 1. Sequential FLAIR (fluid-attenuated inversion recovery) MR images of the brainGoldenberg, P. C. et al. Neurology 2003;60:

46 LEIGH - Multiple specific causesGenerally defects in energy metabolism Lactate elevated in most patients in some phase of illness, CSF > blood

47 LEIGH - Genetics Usually due to nuclear gene mutation (autosomal recessive) Minority due to mitochondrial DNA abnormality (maternal)

48 INFANTILE NEUROAXONAL DYSTROPHY (INAD)Onset age 6 months-3 years (classic form) Slowly progressive Combination of lower, then upper motoneuron signs: Falling, clumsiness Hypotonia, hyporeflexia with normal NCV's Later, spasticity

49 INFANTILE NEUROAXONAL DYSTROPHYAlso later Optic atrophy, blindness Involuntary movements, dystonia, decerebrate rigidity Dementia Seizures occur in a minority of pts NCV's normal; EMG's suggest denervation Autosomal recessive

50 INFANTILE NEUROAXONAL DYSTROPHYIron in globus pallidus in 40-50% Cerebellar atrophy

51 INFANTILE NEUROAXONAL DYSTROPHYPathology Axonal spheroids in medulla (cuneate, gracilis), pons, thalamus, and peripheral nerve

52 INFANTILE NEUROAXONAL DYSTROPHYOptic atrophy and MRI are helpful in suspecting diagnosis Resembles PKAN (pantothenate kinase-associated neurodegeneration; Hallervorden-Spatz) but no “eye of the tiger” sign Diagnosis in the past: skin or conjunctival biopsy; spheroids in nerves PLA2G6 mutations found in 95% of patients (gene found 2006) Calcium-independent phospholipase A2, catalyzing the hydrolysis of glycerophospholipids, probably causing membrane pathology

53 "CEREBRAL" GM1 GANGLIOSIDOSIS (TYPE II)Normal until 6-14 months, then regress Hyperacusis, ataxia, dysarthria, strabismus Then mental regression, spasticity, and seizures No organomegaly or macular degeneration ß-galactosidase deficiency

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55 INFANTILE NEURONAL CEROID LIPOFUSCINOSIS (Santavuori-Haltia)Onset 2nd year of life; occasionally by 8 months Rapid deterioration (weeks to months) Myoclonus Visual loss; retinal degeneration; blind by age 2-3 Dementia Loss of motor skills

56 INFANTILE NEURONAL CEROID LIPOFUSCINOSISAcquired microcephaly and severe cerebral atrophy Vegetative state, with death usually by 5-10 years Seizures occur, but not prominent Leukocytes, skin, conjunctiva, rectum: granular inclusions

57 CASE Rett

58 INFANTILE, WITH VISCERAL STORAGEGeneralized GM1 gangliosidosis Gaucher's (infantile) Niemann Pick, type A Sandhoff Wolman's Glycolipid and glycoprotein disorders (fucosidosis, mannosidosis, sialidosis, I-cell disease)

59 GENERALIZED GM1 GANGLIOSIDOSIS (TYPE I)Feeding difficulty plus failure to thrive noted soon after birth Poorly responsive Hypoactive Hypotonic Hyperacusis Cherry-red spot in about half

60 GENERALIZED GM1 GANGLIOSIDOSIS (TYPE I)Edema of face and extremities Bone changes Long bones wide in center, tapered at end Vertebral hypoplasia and beaking Hepatosplenomegaly Corneas clear Store ganglioside in brain and mucopolysaccharide in viscera and bone ß-galactosidase deficiency Usually die in first 1-2 years Like Tay Sachs and Hurler combined

62 GAUCHER DISEASE (TYPE II)Irritability Later signs and symptoms Dementia Spasticity Ataxia Rare seizures Trismus and stridor Normal fundi

63 GAUCHER DISEASE (TYPE II)Splenomegaly > hepatomegaly Bones thinned; pathologic fractures common Pulmonary infiltrates Do not have Hurler phenotype Glucocerebrosidase deficiency

64

65 GAUCHER DISEASE (TYPE II)Can diagnosed by Gaucher cells in bone marrow Neuropathology: Little lipid storage Neuron loss, especially in brainstem

66 GAUCHER DISEASE (Type I; Adult)Most common Nervous system not involved Treatment with Replacement enzyme Miglustat (Zavesca) Inhibitor of glucosylceramide synthase, needed for synthesis of most glycospingolipids Prevents accumulation of glucosylceramide Also used in other forms of Gaucher, NP-C, GM1, and Tay Sachs

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68 NIEMANN-PICK DISEASE, TYPE A (ACUTE NEUROPATHIC)Like Gaucher's, plus cherry-red spot in ~25-50% Onset 3-9 months of life Hepatomegaly > splenomegaly (often initial presentation) Progressive intellectual and motor deterioration Feeding difficulty and failure to thrive Seizures infrequent

69 NIEMANN-PICK DISEASE, TYPE A (ACUTE NEUROPATHIC)Pathology Ballooned neurons Vacuolated histiocytes and lymphocytes (Niemann-Pick cells) Sphinomyelinase deficiency Autosomal recessive Frequently Jewish

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71 CASE Visceromegaly Hexosaminidase A & B deficiency Sandhoff

72 LATE INFANTILE, WITHOUT VISCERAL STORAGENeuronal ceroid lipofuscinosis Juvenile Tay-Sachs Progressive myoclonus epilepsies Huntington's chorea Xeroderma pigmentosa

73 NEURONAL CEROID LIPOFUSCINOSISUsually autosomal recessive Numerous eponyms, mixed features Enzyme and genetic testing has generally replaced biopsies Defects in lysosomal function

74 NEURONAL CEROID LIPOFUSCINOSISType Infantile: INCL, CLN1 Late-infantile: LINCL, CLN2 Juvenile: JNCL, CNL3 Adult: ANCL, CNL4, 5 Eponyms Santavuori-Haltia Jansky-Bielschowsky Spielmeyer-Sjögren; Spielmeyer-Vogt; Batten Kufs (AR) Parry (AD) Usual age of onset 6-24 months 2-4 years 4-10 years Variable; usually 2nd-3rd decade Course Rapid Slower Slow Age at death 5-10 years 8-12 years 15-25 years Variable Manifesting symptoms Myoclonus, visual loss Seizures, particularly myoclonic Visual loss, dementia Extrapyramidal signs, ataxia Other symptoms Dementia, seizures, ataxia, acquired microcephaly Ataxia, dementia, late visual loss Seizures (less prominent), dysarthria, extrapyramidal signs Myoclonus, dysarthria, seizures, personality changes, neuropathy Retina Nonpigmentary degeneration Pigmentary degeneration Normal* ERG Decreased Absent VER Increased Membranous inclusions Granular Curvilinear or rectilinear Fingerprints; vacu-olated lymphocytes

75 NEURONAL CEROID LIPOFUSCINOSISType Infantile: INCL, CLN1 Late-infantile: LINCL, CLN2 Juvenile: JNCL, CNL3 Adult: ANCL, CNL4, 5 Eponyms Santavuori-Haltia Jansky-Bielschowsky Spielmeyer-Sjögren; Spielmeyer-Vogt; Batten Kufs (AR) Parry (AD) Enzymatic defect Palmitoyl protein thioesterase (PPT) Pepstatin-insensitive lysosomal peptidase—tripeptyidyl peptidase 1 (some pts) CLN3 protein; trans-membrane chaparone, involved in folding of other proteins ? Also PPT in one family Lysosomal accumulation Sapsosin A, B Subunit C of mitochondrial ATP Genetic defect CLN1/PPT1 1p32 CLN2/TPP1 11p15.5 CLN3 16p12.1 CLN4 Mixed findings

76 From Genetests.org Epilepsy gene panel!

77 NEURONAL CEROID LIPOFUSCINOSIS PathologyAtrophy of both gray and white matter Cerebral > cerebellar Cerebellar prominent in CLN2 Almost complete loss of cortical neurons in CLN1 Lipopigments in neurons, glia, endothelial cells, liver, skin, WBCs, etc. Retinal necrosis; almost complete loss of photoreceptors

78 NEURONAL CEROID LIPOFUSCINOSIS PathologyVacuolated lymphocytes in CLN3

81 Bovine model of NCL Retina atrophy

82 Granular osmophilic deposits

83 Curvilinear inclusions

84 Fingerprint inclusions

85 NEURONAL CEROID LIPOFUSCINOSIS ImagingAtrophy Hypointense thalami on T2 Progressive WM signal on T2 ↓ ↓ N-acetylaspartate on MRS

86 Now 14 NCL variants

87 JUVENILE TAY-SACHS (PARTIAL GM2 GANGLIOSIDOSIS)Variant 1 Typical "gray matter disease“ Seizures and dementia Cerebellar and basal ganglia dysfunction No cherry-red spot Onset years, with 5-10 year course Variant 2 More like spinocerebellar degeneration Onset between age 2 and adulthood

89 LATE INFANTILE, WITH VISCERAL STORAGEGaucher Type III Niemann Pick, type C Mucopolysaccharidoses Hurler's Hunter's Sanfilippo's

90 GAUCHER DISEASE (Type III; Chronic Neuronopathic)Slower course Onset early childhood to adult Mild to severe mental retardation Seizures and myoclonus (progressive myoclonus epilepsy) Spasticity Cranial nerve dysfunction Eye movment abnormalities (e.g., oculomotor apraxia with failure of saccadic initiation, supranuclear gaze palsy) Splenomegaly

91 NIEMANN-PICK, TYPE C (CHRONIC NEUROPATHIC)Similar to type A but onset later (> 2 years) and slower progression Can have hepatic disease due to cholestasis even in neonatal period Mild splenomegaly Dementia Marked spasticity Apraxia of vertical gaze

92 NIEMANN-PICK, TYPE C Ataxia CataplexyGeneralized tonic-clonic and myoclonic seizures Some with cherry-red spot Most die before age 10-15 Sphinomyelinase deficiency

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94 Cherry red spots can be seen in all but which of the following disorders?A. Tay Sachs B. Generalized GM1 Gangliosidosis C. Infantile Neuroaxonal Dystrophy D. Niemann Pick type A E. Farber lipogranulomatosis

95 A 3-month-old boy comes in with seizures, subdural hemorrhages, and rib fractures. What metabolic disorder should be suspected? A. Leigh B. Niemann-Pick type A C. Alper D. Menke

96 3. Match the disorder with other organ involvement:Alper Retina Pompe Heart Neuronal ceroid lipofuscinosis Blood vessels Gaucher Liver Farber lipogranulomatosis Joints Menke Spleen

97 Which symptom is not common in girls with Rett syndrome?A. Perseverative speech B. Hand wringing C. Bruxism D. Hyperventilation E. Aerophagia

98 5. Match the disease and the gene or enzyme:Rett Hexosamindase A Alper PLA2G6 Tay Sachs Acid maltase Niemann Pick Mitochondrial DNA polymerase gamma (POLG) Pompe MeCP2 Infantile neuroaxonal dystrophy Sphingomyelinase

99 6. Which of the following is considered a mitochondrial disorder?A. Pompe B. Leigh C. Tay Sachs D. Gaucher E. Neuronal ceroid lipofuscinosis

100 Extra-pyramidal sx’s, ataxia7. For each of the neuronal ceroid lipofuscinoses, check off the most prominent initial symptoms. Seizures Visual loss Myoclonus Dementia Extra-pyramidal sx’s, ataxia Infantile Late infantile Juvenile Adult

101 Extra-pyramidal sx’s, ataxia7. For each of the neuronal ceroid lipofuscinoses, check off the most prominent initial symptoms. Seizures Visual loss Myoclonus Dementia Extra-pyramidal sx’s, ataxia Infantile  Late infantile Juvenile Adult

102 Extra-pyramidal sx’s, ataxia7. For each of the neuronal ceroid lipofuscinoses, check off the most prominent initial symptoms. Seizures Visual loss Myoclonus Dementia Extra-pyramidal sx’s, ataxia Infantile  Late infantile Juvenile Adult

103 Extra-pyramidal sx’s, ataxia7. For each of the neuronal ceroid lipofuscinoses, check off the most prominent initial symptoms. Seizures Visual loss Myoclonus Dementia Extra-pyramidal sx’s, ataxia Infantile  Late infantile Juvenile Adult

104 Extra-pyramidal sx’s, ataxia7. For each of the neuronal ceroid lipofuscinoses, check off the most prominent initial symptoms. Seizures Visual loss Myoclonus Dementia Extra-pyramidal sx’s, ataxia Infantile  Late infantile Juvenile Adult

105 8. Name the metal associated with the disease:A. Menke: Copper B. Infantile Neuroaxonal Dystrophy: Iron

106 9. Match the disease and pathological finding:Infantile neuroaxonal dystrophy Glycogen storage Alper Pili torti Tay Sachs Ballooned cells with “torpedoed” axons Neuronal ceroid lipofuscinosis Spheroids Pompe Curvilinear, fingerprint, and granular osmophilic inclusions Menke Laminar cortical degeneration

107 Case #1: girl with slow regressionNormal motor and cognitive development until age 2 Then gradually lost ability to verbalize, with slower loss of comprehension Progressive ataxia and weakness. Using walker by age 3. Stopped crawling by age 4. Exam: No HSM. Followed a few commands. Nonverbal. Hypotonic but with spastic catch. Weak. Hyporeflexic. Ataxic. Later, visual loss, seizures, hypertonicity, hyperreflexia MRI: cerebellar and brainstem atrophy EMG and nerve bx: mild axonopathy Died age 10 Dx: infantile neuroaxonal dystrophy INAD

108 INFANTILE NEUROAXONAL DYSTROPHY (INAD)Onset age 6 months-3 years (classic form) Slowly progressive Combination of lower, then upper motoneuron signs: Falling, clumsiness Hypotonia, hyporeflexia with normal NCV's Later, spasticity

109 INFANTILE NEUROAXONAL DYSTROPHYAlso later Optic atrophy, blindness Involuntary movements, dystonia, decerebrate rigidity Dementia Seizures occur in a minority of pts NCV's normal; EMG's suggest denervation Autosomal recessive

110 INFANTILE NEUROAXONAL DYSTROPHYIron in globus pallidus in 40-50% Cerebellar atrophy

111 Case #2: girl with slow regressionHistory of 32-week prematurity and neonatal hepatitis, HSM that resolved. Started walking at 17 months, always a toe-walker. Delayed but could ride a bike at age 5. Seizures starting at 18 months. Age 6 began to have spells of becoming limp and falling when she was excited. When she presented to us at age 5, she was microcephalic, and had oculomotor apraxia, truncal hypotonia but tight heel cords, dysmetria and ataxia. Progressive ataxia, dysphagia, loss of speech, and loss of ability to voluntarily look up, then down (but could be “dolled”). Died age 10 Dx: Niemann-Pick, type C NP-C

112 NIEMANN-PICK, TYPE C (CHRONIC NEUROPATHIC)Similar to type A but onset later (> 2 years) and slower progression Can have hepatic disease due to cholestasis even in neonatal period Mild splenomegaly Dementia Marked spasticity Apraxia of vertical gaze

113 NIEMANN-PICK, TYPE C Ataxia CataplexyGeneralized tonic-clonic and myoclonic seizures Some with cherry-red spot Most die before age 10-15 Sphinomyelinase deficiency

114 Case #3 – boy with rapid regressionNormal until 7 months Then low grade fever without source, fussy, and regressed Stopped rolling, scooting; lost head control. Weaker on left. Initially very floppy but progressively hypertonic. Regressed episodically. Frequent fevers. Progressive dysphagia, and stopped feeding. Hyperventilation. Infantile spasms Leigh

115 Brother with same problem but slower progressionNo known consanguinity but from “very stable community” Exam: truncal hypotonia, limb hypertonia, brisk DTRs Lactate 29 (up to 2.2); pyruvate 1.2 MRI: high T2 signal in basal ganglia Brother had similar MRI

116

117 Died age 2-1/2 Brother died age 14 years Dx: Leigh syndrome

118 LEIGH SYNDROME (subacute necrotizing encephalomyelopathy)Onset in early infancy (60% in 1st year) or childhood; rarely in adulthood Neonatal form Acidosis Severe retardation Usually early death Other types with variable clinical picture: Steadily progressive, saltatory, or episodic May progress with intercurrent infections Typically associated with lactic acidosis

119 LEIGH – Symptoms and signsRetarded motor and intellectual development Respiratory disturbances Ophthalmoplegia Dysphagia and weight loss Vomiting Hypotonia & weakness Ataxia

120 LEIGH – Symptoms and signsSeizures Visual loss Nystagmus Dystonia Peripheral neuropathy (often subclinical) Fevers

121 LEIGH - Pathology Brainstem and basal ganglia lesions commonNecrosis around 4th ventricle and aqueduct. Distribution resembles Wernicke's without mammilary bodies and without hemorrhage

122 Figure 1. Sequential FLAIR (fluid-attenuated inversion recovery) MR images of the brainGoldenberg, P. C. et al. Neurology 2003;60:

123 Case #4 – a true unknown! How would you work him up?11 y.o. boy seen in clinic for developmental decline and myoclonus PLD normal Early development normal; “riding two-wheeler at age 2” Age 4: began to be rigid in his routines; sensitive to a variety of stimuli KG: reading 10 words, c/w 20-word average; not counting as high

124 Age 6: 1st seizure; clonic; focal EEG (posterior) Development plateaued Seizure-free on oxcarb until age 10 Then recurrent clonic seizures, affecting either or both sides of body Frequent generalized myoclonic jerks Starting at age 10, progressive ataxia, cognitive loss, dysarthria Now crawls to ambulate Comprehension ok and good sense of humor; difficulty thinking of words

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126 News since the 2014 talk! Work-up? Late infantile NCL (Epi gene panel)Whole exome analysis News since the 2014 talk! Late infantile NCL (Epi gene panel)

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130 Case #2 GM

131 Case #4 Juvenile TS

132 Tips for next talk Add CDG? 33051487 – no; do as clinic 10:00 case.Timing was fine. A little dry in the middle. Cases are good idea. Perhaps add a brief case at the end of each of the 4 sections.