IMAGING IN INHERITED METABOLIC DISORDERS PART-2.pptx

INERITED METABOLIC DISORDER

1. IMAGING IN INHERITED METABOLIC DISORDERS PART-2 Moderator:Dr N L Rajendra kumar Presenter: Dr Raksha A R

2. Introduction IMDs Predominantly Affecting Gray Matter a ) involve the cortex and b ) those that mostly affect the deep gray nuclei . Disorders Affecting Both Gray and White Matter Mucopolysaccharidoses Mitochondrial Diseases (Respiratory Chain Disorders ) Urea Cycle/Ammonia Disorders Methylmalonic and Propionic Acidemias Congenital Glycosylation Disorders Summary References

3. Introduction Inherited metabolic disorders (IMDs) — also known as inborn errors of metabolism —represent conditions in which a genetic defect leads to a deficiency of a protein (e.g., enzyme or non-enzyme protein ) that subsequently affects mechanisms of synthesis , degradation, transport, and/or storage of molecules in the body . Rapid therapeutic intervention can avoid irreversible brain injury.

4. IMDs Predominantly Affecting Gray Matter Inherited metabolic disorders (IMDs) that involve the gray matter (GM) without affecting the white matter (WM) are also known as poliodystrophies . They can be subdivided into those that a) involve the cortex and b) those that mostly affect the deep gray nuclei. Inherited GM disorders that involve the deep gray nuclei are significantly more common than those that primarily affect the cortex.

5. IMDs Primarily Affecting Deep Gray Nuclei Three inborn errors of metabolism with specific predilection for the deep gray nuclei include (1) pantothenate kinase-associated neurodegeneration (PKAN ), (2) creatine deficiency syndromes , and (3)cytosine- adenineguanine (CAG ) repeat disorder called Huntington disease . Two inherited disorders with abnormal copper metabolism, Wilson disease and Menkes disease .

6. Brain Iron Accumulation Disorders Neurodegeneration with brain iron accumulation ( NBIA) represents a group of conditions characterized by progressive neurodegeneration and abnormally elevated brain iron . Four major NBIA subtypes have been defined at the molecular genetic level: ( 1) PKAN (or NBIA type 1), (2) neuroferritinopathy (NBIA type 2), ( 3) infantile neuroaxonal dystrophy , and (4) aceruloplasminemia .

7. Pantothenate kinase-associated neurodegeneration (PKAN ) Formerly known as Hallervorden - Spatz disease . Rare familial autosomal-recessive disorder characterized by excessive iron deposition in the globus pallidus (GP) and substantia nigra (SN). Mutations in the pantothenate kinase gene ( PANK2 ) 50% of the cases occur sporadically .

8. Clinical presentation: 4 clinical forms infantile,late-infantile,juvenile or " classic“ and adult onset NBIA type 1 . Progressive gait disturbances, delayed psychomotor development. Choreoathetosis , dysarthria, and dystonia, Progressive mental deterioration finally leads to dementia

9. T2W GRE

10. Differential Diagnosis. Aceruloplasminemia and neuroferritinopathy are both adult-onset disorders. Both involve the cortex . Inherited metabolic disorders to consider in the differential diagnosis of BG T2 hyperintensity include, Methylmalonic acidemia (increased T2 signal in GP + WM T2 prolongation ), Canavan disease (GP and other deep nuclei showing increased T2 signal, subcortical WM T2 hyperintensity , and increased NAA:Cr ) Guanidinoacetate methyltransferase deficiency (GAMT) (with or without GP T2 hyperintensity , absent or severely reduced Cr on MRS), Neuroferritinopathy ( variable GP T2 hyperintensity ),

11. DD’s Continued…. Wilson disease, Leigh syndrome, infantile bilateral striatal necrosis, and Mitochondrial encephalopathies - involve caudate and putamen, not the medial GP . Hypoxic ischemic injury (positive health history, T2 hyperintensity involving striatum , GP, thalami, corticospinal tracts, with or without cortical involvement ), CO poisoning (increased T2 signal involving GP, other deep nuclei , cortex, and WM), Cyanide toxicity (T2 increased withinbasal ganglia with or without hemorrhagic necrosis), and Kernicterus ( neonate) (increased T1/T2 GP).

12. Neuroferritinopathy (NBIA type 2 ) Adult autosomal-dominant disorder Mutations in the carboxy terminus of the ferritin light chain gene ( FTL ) interfere with the transport of iron. Clinical features: Extrapyramidal disorder with choreiform movements and focal dystonia Early cognitive and psychiatric disturbances are absent , thus distinguishing neuroferritinopathy from Huntington disease.

13. Imaging features T2 * GRE and SWI hypointensity (" blooming") in the GP and SN . T2 hypointensity in the GP and SN , red nuclei, caudate, putamen , thalamus, and cerebral cortex typically follow . In later stages, gliosis and cystic degeneration in the medial GP may produce foci of T2 hyperintensity that causes an "eye of the tiger" appearance similar to that seen in PKAN.

14. Infantile Neuroaxonal Dystrophy Mutations in phospholipase A2 ( PLA2G6 ) cause infantile neuroaxonal dystrophy (INAD), a severe psychomotor disorder showing progressive hypotonia , hyperreflexia , and tetraparesis . Imaging findings: striking cerebellar atrophy - 95% of cases . T2/FLAIR hyperintensity in the cerebellum secondary to demyelination and gliosis is also common .

15. Aceruloplasminemia . Homozygous mutations in the ceruloplasmin gene cause aceruloplasminemia , also known as hereditary ceruloplasmin deficiency. Playing an important role in mobilizing tissue iron. Aceruloplasminemia is a disease of middle-aged adults characterized by the clinical triad of diabetes, retinopathy, and neurologic symptoms (primarily dementia, craniofacial dyskinesia and cerebellar ataxia).

16. T2* GRE T2* GRE T2* GRE T2* SWI

17. Creatine Deficiency Syndromes Brain creatine deficiency syndromes are a group of rare disorders that include, guanidinoacetate methyltransferase (GAMT) deficiency , -- arginine:glycine amidinotransferase (AGAT) deficiency , and creatine transporter defect ( SLC6A8 ) (CRTR). The first two are inherited in an autosomal-recessive pattern, and the third is an X-linked recessive disorder. Dietary supplementation can partially or completely reverse the symptoms and imaging abnormalities , so making the diagnosis is crucial to patient management .

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20. Differential Diagnosis. Methylmalonic acidemia (increased GP T2 signal and WM T2 hyperintensity ), Neuroferritinopathy ( eye of the tiger and SWI GP blooming ), Canavan disease (macrocephaly, subcortical WM T2 hyperintensity , GP increased T2 signal). Toxic/ischemic insults include HII (health history, striatal and thalamic DWI hyperintensity , with or without watershed ischemia ), CO poisoning (increased GP, other deep nuclei, and WM T2/FLAIR hyperintensities ), and Cyanide poisoning ( hemorrhagic necrosis and basal ganglia increased T2 signal).

21. Huntington Disease

22. Clinical features: Adult-onset HD - progressive loss of normal motor function, development of stereotypic choreiform movements, and deteriorating cognition. Juvenile-onset HD is initially characterized by rigidity and dystonia, much more than by chorea. Cerebellar signs are also common

23. FLAIR NECT

24. Differential Diagnosis For adult HD. Multiple system atrophy (MSA), corticobasal degeneration, and frontotemporal lobar dementia . - basal ganglia atrophy For juvenile HD Leigh syndrome (DWI hyperintensity and increased T2/FLAIR in the putamen , caudate, and tegmentum ), Late-stage Wilson disease (caudate and brainstem atrophy, increased symmetric signal in the caudate nucleus, putamen, midbrain, and pons and regions of caudate and putaminal irregular T2 hypointensities ), and PKAN with choreoathetosis and dementia , which can mimic the symptoms of HD. The " eye of the tiger" sign in the medial GP distinguishes PKAN from HD.

25. Disorders of Copper Metabolism Copper is essential for normal brain development. Copper-containing proteins are a critical element in a number of enzymatic systems, including iron homeostasis. Excess copper is neurotoxic . Two disorders of copper metabolism— Wilson disease (WD) and Menkes disease —have striking CNS manifestations . The major manifestations of WD are found in the basal ganglia, midbrain, and dentate nucleus of the cerebellum.

26. Wilson Disease

27. Clinical features: Early-onset WD (8-16 years of age) are usually related to liver failure. Later-onset WD - primarily neurologic and are generally recognized in the second or third decade Dysarthria , dystonia, tremors, ataxia , Parkinson-like symptoms, and behavioral disturbances are common. Copper deposition in the cornea -characteristic greenish yellow Kayser -Fleischer rings seen on slit-lamp examination

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29. T1W T1+C DWI T2W

30. Differential Diagnosis. Leigh syndrome - shows bilateral, symmetric , spongiform, and hyperintense lesions particularly in the putamen and brainstem. The WM is often affected. Organic aciduria (widened CSF spaces, symmetric WM T2/FLAIR hyperintensities , basal ganglial increased T2 signal) JE (mosquito-borne illness showing characteristic homogeneous T2/FLAIR hyperintensities in the basal ganglia and posteromedial thalami) PKAN can resemble WD. WD predominantly affects the putamina and caudate nuclei rather than the medial GP and lacks the "eye of the tiger" sign often seen in PKAN.

31. Menkes Disease. Also known as kinky hair syndrome—is an X-linked multisystemic , lethal disorder of copper metabolism caused by ATP7A gene mutations . Severe classic Menkes disease –progressive neurodegeneration , connective tissue abnormalities, pili torti (" kinky" hair), and death in early childhood. 90-95 % of cases.

32. T2W NECT T1+C

33. NECT T2W T1W T1W

34. Differential Diagnosis Glutaric aciduria type I (widened lateral cerebral fissures, GP increased DWI and T2/FLAIR signal) , Hypoxic ischemic encephalopathy (HII ) (positive health history, nonprogressive neurologic features ), Urea cycle defects (initial diffuse cerebral edema, looks like "worst case ever" of HII ), TORCH infections (microcephaly , Ca ++, nonprogressive ), Loeys -Dietz syndrome (characterized by aneurysms of the aorta and other vessels , including intracranial, similar to Marfan syndrome).

35. IMDs Primarily Affecting Cortex Disorders that exclusively or primarily affect the cortical GM are rare. Two prototypical IMDs that involve the cortex are, neuronal ceroid lipofuscinoses (NCLs) and Rett syndrome (RTT ).

36. Neuronal Ceroid Lipofuscinosis Heterogeneous family of inherited neurodegenerative disorders characterized by accumulation of ceroid-lipopigment inclusions in neurons . Incidence of 1:12,500 Striking global atrophy with no specific lobar predominance Progressive and selective neuronal loss and gliosis with secondary WM degeneration are universally present.

37. Imaging features: NCLs share common but nonspecific imaging features NECT: Thalami and GP are hyperattenuating and T2WI: Thalami and GP are hypointense Serial MR shows progressive atrophy with thinned cortex, enlarged ventricles, periventricular T2/FLAIR hyperintense rims, and prominent sulci.

38. Differential Diagnosis. HII status marmoratus (positive health history of perinatal hypoxic ischemic insult, nonprogressive hyperattenuating GP and thalami, striatal increased T2 signal, perirolandic atrophy), Krabbe disease ( hyperattenuating on NECT thalami, caudate, and dentate nuclei, increased T2 signal cerebral WM), and Juvenile GM1 gangliosidoses ( hyperattenuating thalami on NECT , T2 hypointensity of ventral thalami, hypointense dorsal thalami ).

39. Rett Syndrome Progressive neurodevelopmental diso rder that almost always affects girls . Mutation in the methyl- CpG -binding protein-2 gene ( MECP2 ) in 80% of cases. Head growth gradually decelerates after the first few months, and severe psychomotor retardation develops. Intellectual impairment, mood and behavioral changes, speech difficulty, truncal apraxia , and stereotypical hand waving develop.

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41. Differential Diagnosis Cortical thinning in NCL is generalized and does not exhibit the frontotemporal pattern seen in RTT. Autism is excluded if the patient is MECP2 mutation positive. Hypoxic ischemic encephalopathy to include watershed infarction is nonprogressive and associated with positive health history.

42. Disorders Affecting Both Gray and White Matter The pathoetiologies are quite variable and range from abnormal organelles to specific enzymatic dysfunctions. Mucopolysaccharidoses (MPSs ), Canavan disease, Alexander disease, Peroxisomal spectrum disorders, and Mitochondrial disorders .

43. Mucopolysaccharidoses Lysosomal storage disorders characterized by incomplete degradation and progressive accumulation of toxic glycosaminoglycan (GAG) in various organs. MPS 1H (Hurler) and MPS 1HS (Hurler- Scheie disease) have deficiency of α-L- iduronidase (4p16.3). MPS 2 (Hunter disease) is characterized by iduronate 2-sulfatase deficiency (Xq28). MPS 3A ( Sanfilippo disease) , a deficiency of heparin N- sulfatase (17q25.3 ), MPS 4A ( Morquio disease) , a deficiency in galactose 6-sulfatase (16q24.3), MPS 6 ( Maroteaux-Lamy disease) associated with a deficiency in arylsulfatase B (5q11-q13).

44. The two distinctive gross features of the MPSs are thickened meninges and dilated perivascular spaces (PVSs) . Clinical features: Macrocrania , coarse facies , bushy eyebrows , frontal calvarial bossing , J-shaped sella , enlarged PVSs, WM abnormalities, pachymeningopathy , impacted teeth, macroglossia , flat nasal bridge, hepatosplenomegaly , and skeletal dysostoses

45. Imaging features: Macrocephaly: NECT and MR scans show an enlarged head, often with metopic " beaking " and scaphocephalic configuration Reduced attenuation of WM, progressive hydrocephalus, and atrophy of Virchow-Robin spaces, large head with craniofacial disproportion Enlarged Perivascular Spaces and WM Abnormalities: Striking sieve-like cribriform appearance in the posterior cerebral WM and corpus callosum is characteristic and is caused by numerous dilated PVSs "Hurler holes,“( typical of both Hurler and Hunter diseases)

46. NECT FLAIR T2W T2W

47. Differential Diagnosis Normal findings common in middle-aged and older patients. Velocardiofacial syndrome : Dilated PVSs with a frontal predominance . Deviated carotid arteries in the pharynx are present, a finding not associated with the MPSs. Hypomelanosis of Ito may show dilated PVSs. Cutaneous hypopigmented zones with irregular borders are seen; seizures develop in the first year of life.

48. Peroxisomal Biogenesis Disorders Abnormal formation of peroxisomes Four major PBDs are recognized: Zellweger syndrome ( ZS, also called cerebrohepatorenal syndrome ), Neonatal adrenoleukodystrophy , Infantile Refsum disease, and Classic rhizomelic chondrodysplasia punctata . The first three disorders are grouped together and referred to as Zellweger syndrome spectrum (ZSS).

49. Autosomal-recessive disorders caused by mutations in one of 13 peroxisomal assembly ( PEX ) genes. Gross findings are cerebral neocortical and cerebellar abnormalities. Clinical features: Dysmorphic facies with large fontanelle and sutures, high forehead , and broad nasal bridge. Hepatointestinal dysfunction , hypotonia ("floppy infant"), seizures, retinitis pigmentosa , and psychomotor retardation are common.

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51. Differential Diagnosis Congenital cytomegalovirus ( CMV)- Calcifications along the caudostriatal groove, and the periventricular cysts. Isolated neuronal migration disorders (e.g., bilateral perisylvian polymicrogyria ) Pseudo-TORCH shows basal ganglia, brainstem , thalamic, and periventricular Ca ++.

52. Mitochondrial Diseases ( Respiratory Chain Disorders) Caused by mitochondrial DNA ( mtDNA ) mutations Four major encephalomyopathic syndromes have been described : Leigh syndrome , Kearns-Sayre syndrome , MELAS , and MERRF Glutaric aciduria types 1 and 2, also caused by mtDNA-mediatedenzyme abnormalities ]

53. Leigh Syndrome Leigh syndrome (LS) is also known as subacute necrotizing encephalopathy caused by mutations that encode for OXPHOS enzymes, a group of disorders caused by defective terminal oxidative metabolism . CINICAL FEATURES : Failure to thrive, central hypotonia,developmental regression, ataxia, bulbar dysfunction, and ophthalmoplegia . Serum and/or CSF lactate levels are increased

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55. Differential Diagnosis MELAS typically shows stroke-like abnormalities in the cortical gray matter in a nonvascular distribution in the hemisphere. Metabolic and hypoxic-ischemic disease can mimic some findings of LS. Wilson disease (WD) shows T2/FLAIR hyperintensity in the putamina , midbrain , and thalami. Perinatal asphyxia (HII ) can affect the basal ganglia and mimic LS, and the corticospinal tracts and perirolandic cortex are commonly affected.

56. MELAS Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is caused by several different point mutations. The clinical triad of lactic acidosis, seizures, and stroke-like episodes is the classic MELAS is an uncommon but important cause of childhood stroke. Prevalence 1.2-13.0 cases/100,000 live births.

57. DWI T2W T2W

58. Differential diagnosis Cerebral infarction . Prolonged seizures MERRF shows a propensity to involve the basal ganglia, caudate nuclei, and vascular watershed zones. Certain vitamin deficiencies

59. Kearns-Sayre Syndrome Also known as Kearns-Sayre ophthalmoplegic syndrome, is another mtDNA disorder. The most typical and consistent pathologic finding is spongiform WM vacuolation . The cerebral hemispheres and midbrain are most commonly affected whereas the corpus callosum and internal capsules are usually spared Differential diagnosis: MELAS . Early involvement of the cortex in a nonvascular distribution—particularly the parietal and occipital lobes—is characteristic of MELAS

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61. MERRF Myoclonus epilepsy with ragged red fibers (MERRF) is another syndrome with mtDNA mutations that result in defective mitochondrial OXPHOS. MERRF is a multisystem disorder characterized by myoclonus (often the first symptom ) followed by epilepsy, ataxia, weakness, cardiomyopathy, and dementia . Imaging feature: Watershed and basal ganglia infarcts . Differential diagnosis: MELAS and KSS

62. Glutaric Aciduria Type 1 Autosomal-recessive IMD - deficiency of the mitochondrial enzyme glutaryl -coenzyme A dehydrogenase ( GCDH) . Clinical features: Macrocephaly at birth Acute encephalopathy , seizures, dystonia, choreoathetosis , vomiting, and/or opisthotonus . These episodic crises are triggered by febrile illness, immunization , or surgery Therapy for GA1 requires limitation of lysine and tryptophan and administration or oral carnitine .

63. DWI T2W T2W

64. Differential Diagnosis. Subdural hemorrhage occurring in the setting of abusive head trauma. Hydrocephalus, benign expansion of the subarachnoid spaces (BESS) of infancy , benign familial macroceph aly (a normal variant ), middle cranial fossa arachnoid cysts (i.e., usually unilateral), and IMDs- mucopolysaccharidoses (CSF-like mucopolysaccharide pachymeningeal deposition in all but Morquio type 4 MPS), Canavan disease , and Alexander disease.

65. Glutaric Aciduria Type 2 Defect in the mitochondrial electron transport chain at coenzyme Q . Three phenotypes :neonatal onset with multiple associated congenital anomalies, neonatal onset without anomalies , and late-onset form. Imaging Findings. T2/FLAIR hyperintensity involving the corpus striatum, caudate nucleus, putamen, middle cerebral peduncles , splenium of the corpus callosum, and hemispheric WM. " open" sylvian fissures absent in GA2 . Differential Diagnosis: Diabetic ketoacidosis Profound hypoxic ischemic injury (HII )

66. Urea Cycle/Ammonia Disorders Interruption of the urea cycle results in elevated serum ammonia, which readily crosses the blood-brain barrier and causes diffuse cerebral edema. In chronic disease, atrophy with resultant ulegyria is seen . Two classic and most common disorders are ornithine transcarbamylase deficienc y ( OTCD)and citrullinemia and both show diffuse brain swelling (which does not spare the basal ganglia) on NECT and MR scans.

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69. Differential Diagnosis Hypoxi ischemic encephalopathy ( HIE)( typically have more thalamic and perirolandic cortical abnormalities) . Neonatal herpes simplex encephalitis (i.e ., usually HSV type 2 ) is often associated with hepatitis and diffuse pulmonary involvement.(non-patterned and may present with diffuse edema).

70. Methylmalonic and Propionic Acidemias Autosomal-recessive disorders that both present early in life with episodic ketoacidosis, lethargy, tachypnea , nausea, vomiting, progressive hypotonia , and seizures , eventually progressing to coma and death. Methylmalonic acidemia is caused by mutation of the MUT gene located at 6p21 , which encodes methylmalonic CoA mutase . Propionic acidemia is caused by mutations in the gene encoding propionyl -CoA carboxylase, PCCA.

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72. Differential Diagnosis Hypoxic ischemic injury (HII) of the profound type involves striatum and thalami as well as corticospinal tracts and hippocampi . Carbon monoxide poisoning targets the BG and is associated with often deep GM structures showing T2 prolongation

73. Gangliosidoses Include GM1 and GM2 [ Tay -Sachs (TS), Sandhoff disease (SD), and GM2 variant AB ]. They are biochemically distinct but clinically indistinguishable. GM1 :rare lysosomal storage disease caused by deficiency of the lysosomal enzyme β- galactosidase results in accumulation GM1 ganglioside in the brain (mainly BG) and oligosaccharide in the abdominal viscera. GM2 is an autosomal-recessive disorder of sphingolipid storage caused by a deficiency of hexosaminidase . Most common infantile form, initial psychomotor retardation and hypotonia are followed by neurologic deterioration. Progressive weakness, choreiform movements , dystonia, and ataxia occur.

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75. Differential Diagnosis HII (status marmoratus ) demonstrates atrophic hyperattenuating thalami, atrophic striatum, and perirolandic cortex . Krabbe disease demonstrates hyperattenuating thalami, caudate, and dentate nuclei. T2 prolongation involves the cerebral and cerebellar WM.

76. Fabry Disease Fabry disease is an X-linked lysosomal storage disorder of glycosphingolipid metabolism . Mutation in α- galactosi dase leads to abnormal accumulation of glycosphingolipids in vascular endothelium and smooth muscle cells . 85 % of strokes in Fabry disease are ischemic strokes

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78. Differential Diagnosis Fahr disease causes bilateral, dense, thick calcifications in the BG and thalami. The cerebellum and GM-WM interfaces are frequently affected but generally not involved in Fabry disease . Endocrinologic disorders like hyperparathyroidism, hypoparathyroidism , pseudohypoparathyroidism , and hypothyroidism may have similar calcifications but lack the multifocal infarcts typical of Fabry disease.

79. Congenital Glycosylation Disorders Autosomal recessive in inheritance - mutation in the gene encoding PMM2 (most common ). CDG ranges from severe infantile multisyste involvement to mild late-onset forms, with hypotonia , developmental delay, failure to thrive, stroke-like episodes, strabismus, ataxia, abnormal subcutaneous fat distribution and nipple retraction.

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81. Differential Diagnosis Ataxia-telangiectasia (with oculomucocutaneous telangiectasias , scattered WM foci of T2 hyperintensity and SWI hypointensity ) GM2 gangliosidosis (showing characteristic T1WI and T2WI findings of the thalami), and Wilson disease (showing tortuous intracranial vessels (corkscrew) and cerebral and cerebellar atrophy and wormian bones).

82. Summary IMDs are relatively uncommon diseases that pose diagnostic dilemmas for clinicians and radiologists alike. Patients usually present with acute encephalopathy and diverse abnormal laboratory findings. Diffusion-weighted imaging and MR spectroscopy provide functional information and improve the imaging diagnosis. Therefore, the diagnostic approach should include comprehensive MR imaging, as well as assessment of the clinical manifestations and proper screening tests for adequate emergency treatment. If the IMD diagnosis is associated with a defined pattern of inheritance, this information is essential to parents who may be considering having other children.

83. References OSBORN’S BRAIN-IMAGING, PATHOLOGY, AND ANATOMY-second edition- Anne G. Osborn . Devastating Metabolic Brain Disorders of Newborns and Young Infants - Hyun Jung Yoon et al, RadioGraphics 2014; 34:1257–1272 Neonatal Neuroimaging Findings in Inborn Errors of Metabolism- Andrea Poretti et al, Journal of magnetic resonance imaging, 2012 Wiley Periodicals