Clinical and imaging diagnosis for heredodegenerative diseases

Handbook of Clinical Neurology, Vol. 111 (3rd series) Pediatric Neurology Part I O. Dulac, M. Lassonde, and H.B. Sarnat, Editors © 2013 Elsevier B.V. All rights reserved

Chapter 6

Clinical and imaging diagnosis for heredodegenerative diseases NATHALIE BODDAERT1*, FRANCIS BRUNELLE1, AND ISABELLE DESGUERRE2 Department of Pediatric Radiology, Hoˆpital Necker Enfants Malades and Medical Faculty, Universit Paris Descartes, Paris, France

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Department of Pediatric Neurology, Hoˆpital Necker Enfants Malades and Universit Paris Descartes, Paris, France

INTRODUCTION

Magnetic resonance imaging

Neurological symptoms are very frequent in inborn errors of metabolism and encompass progressive psychomotor retardation, seizures, and a number of neurological abnormalities in both central and peripheral systems, sensorineural defects, and psychiatric symptoms. Many types of states of coma can reveal inborn errors of metabolism, including those presenting with focal neurological signs. Some patients with organic acidemia and urea cycle defects present with focal neurological signs or cerebral edema. These patients can be mistakenly diagnosed as having cerebrovascular events, cerebral tumor, or even encephalitis in case of fever that is a frequent cause of decompensation. Clinical data and brain imaging are frequently a major key for diagnosis guiding metabolic and genetic investigations. These diseases are classified according to age at onset, eventual extraneurological signs, the neurological presentation, and imaging of the brain.

This method is free from radiation hazard. The procedure takes about 20 minutes to complete. MRI provides images that localize proton nuclei and enable different brain components to be distinguished according to their individual chemical and cellular composition (based on a number of magnetic properties). When placed in a strong magnetic field, the protons of water and fat behave like small magnets and align along the applied external field. The spins regain their equilibrium by emitting radio signals that can be detected and processed into an image. The spins absorb energy from the externally applied radio waves and are converted to an excited state. As they return to a lower state, they release energy in a process called relaxation. The rate of relaxation can be described as an exponential decay. Two fundamental parameters are used to describe this decay of MRI signals: T1 (longitudinal relaxation) and T2 (transverse relaxation). Differences in the T1 and T2 relaxation time of tissues are the primary basis of contrast in clinical MRI. With MRI, the precise structure of the brain can be demonstrated in various planes including sagittal, axial, and coronal sections. Gray matter, white matter, CSF, meninges, and blood vessels are distinguished with a contrast resolution greater than can be provided by CT scan. Bone and calcifications (which have a very low content of free water) do not generate any signal. Intravascular injection of gadolinium outlines intracranial structures that have no blood brain barrier as meninges, choroids plexi, pituitary gland, and tissue in which the blood brain barrier is altered. MRI can also detect the random motion of water molecules: diffusion-weighted imaging. It can detect cytotoxic edema and early ischemic

Computed tomography scan In CT scans, an x-ray source and a detector are rotated around the head of the patient, and anatomical images are generated based on differences in radiodensity. The CT scan provides successive images of tissue, bone, CSF, and blood in parenchyma, ventricles or the subarachnoid space. It provides fine investigation of blood vessels if contrast is injected (angio scanner). Calcifications can be easily disclosed. Although the CT scan does not measure intracranial pressure, it is useful in an emergency.

*Correspondence to: Nathalie Boddaert, Department of Pediatric Radiology, INSERM U1000, Hoˆpital Necker 149 rue de Se`vres, 75015 Paris, France. E-mail: [email protected]

Enfants Malades,

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changes, and also inflammatory edema. MRI may be used to measure brain perfusion (semiquantitative measures). MR angiography can detect the flow of blood vessels. FLAIR (fluid attenuated inversion recovery) can give a high signal for parenchymal lesions and signal nulling of CSF. Some sequences as T1 FSPGR (Fast spoiled gradient) can provide high anatomical resolution, which is useful for surgical localization and to detect subtle lesions (dysplastic). T2* is a sequence that permits the detection of brain iron deposits. R2* is a method used to quantify iron content in the brain. The changes of R2* directly reflect the variations of local iron concentration (Boddaert et al., 2007).

Magnetic resonance spectroscopy Magnetic resonance spectroscopy (MRS) most commonly uses the magnetic properties of protons and is in fact 1H MRI. The protons that contribute to the signal intensity on the images are mainly present in water and fat. N-acetylaspartate (NAA), creatine (Cr), choline (CHO) compounds, lactic acid, and several amino acids can be studied with proton MRS. Additional metabolites that can be detected include myoinositol, glutamate, and glutamine. It is possible to detect the singlet representing the N-acetyl methyl resonance of N-acetylaspartate (NAA) at 2.02 ppm, the methyl and the methylene resonance of total creatine (Cr), including free creatine and phosphocreatine, at 3.02 ppm and 3.93 ppm, respectively, and the methyl resonances of choline-containing compounds (Cho) at 3.22 ppm. Since the singlet resonances of NAA, Cr, and Cho exhibit relatively long T2 relaxation times, they may be specified in spectra at long echo times (135 or 270 ms). When shorter echo times (15–30 ms) are used, a considerably increased number of resonances with short T2 relaxation times can be visualized. Most obvious are the appearance of a strong signal from multiple collapsed resonances of myoinositol (mIns) at 3.56 ppm. A complex pattern of coupled resonances between 2.1 and 2.5 ppm together with a further group of resonances around 3.8 ppm are assigned to glutamine and glutamate. Resonances of g-aminobutyric acid (GABA) are overlapped by the larger resonances of Cr, glutamate, and NAA (GABA resonances at 1.90, 2.30, and 3.03 ppm). Pyruvate is below the level of detection under normal circumstances, but when elevated it gives rise to a single peak at 2.36 ppm. In case of elevated tissue levels of free lipids, for instance as a result of myelin breakdown or spectral contamination by fat from the skull, broad resonances are seen at 0.9 and 1.3 ppm. In the mature brain NAA is almost entirely confined to neurons and their axons. NAA is considered to be a neuron- and axon-specific marker. In disease conditions NAA is often low, related to neuronal or axonal

dysfunction or loss. The Cr peak represents the total amount of creatine and phosphocreatine present in the creatine kinase shuttle. The total creatine pool remains fairly constant under a variety of conditions. For this reason Cr has often been used as internal reference for quantification. Cr is only present intracellularly, and Cr has also been considered a marker for cellular density. A decrease of the creatine peak is seen in creatine metabolism disorders including biosynthesis and cerebral transport defects. Elevated Cho is seen in conditions of high cell density and enhanced membrane turnover, such as brain growth, myelination, demyelination, inflammation, and tumor growth. Cho is also an osmolyte and its level may reflect compensation for osmotic changes. Lactate occupies a special position in energy metabolism. Lactate levels are increased under conditions of anaerobic glycolysis, for example in failure of energy supply or in respiratory chain defects. Elevated lactate is also seen in conditions characterized by the presence of increased numbers of macrophages, such as active demyelination and tissue necrosis.

Diffusion-weighted imaging This MRI-based technique enables the investigation of the orientation of brain pathways in vivo, through characterization of water movements (diffusion) in three-dimensional space. In diffusion-weighted imaging (DWI), each image voxel (three-dimensional pixel) has an image intensity that reflects a single best measurement of the rate of water diffusion at that location. This measurement is more sensitive to early changes after a stroke than more traditional MRI measurements such as T1 or T2 relaxation rates. In axons, water diffusion is impeded by cell walls and myelin sheaths. The apparent diffusion coefficient (ADC) is a measure of this movement. Clinically, trace-weighted images have proven to be very useful to diagnose vascular strokes in the brain, by early detection (within a couple of minutes) of the hypoxic edema.

Diffusion tensor imaging Diffusion tensor imaging (DTI) has been applied to the study of white matter abnormalities and generates tracts such as the pyramidal tract. DTI is important when a tissue such as the neural axons of white matter in the brain has an internal fibrous structure analogous to the anisotropy of some crystals. Water will then diffuse more rapidly in the direction aligned with the internal structure, and more slowly as it moves perpendicular to the preferred direction. This also means that the measured rate of diffusion will differ depending on the direction from which an observer is looking. The properties of each voxel of a single DTI image is usually

CLINICAL AND IMAGING DIAGNOSIS FOR HEREDODEGENERATIVE DISEASES calculated by vector or tensor math from six or more different diffusion-weighted acquisitions, each obtained with a different orientation of the diffusion sensitizing gradients. In addition the directional information can be exploited at a higher level of structure to select and follow neural tracts through the brain a process called tractography. A more precise statement of the image acquisition process is that the image intensities at each position are attenuated, depending on the strength (b-value) and direction of the so-called magnetic diffusion gradient, as well as on the local microstructure in which the water molecules diffuse. More extended diffusion tensor imaging (DTI) scans derive neural tract directional information from the data using 3D or multidimensional vector algorithms based on six or more gradient directions, sufficient to compute the diffusion tensor. The diffusion model is a rather simple model of the diffusion process, assuming homogeneity and linearity of the diffusion within each image voxel. From the diffusion tensor, diffusion anisotropy measures such as the fractional anisotropy (FA) can be computed. Moreover, the principal direction of the diffusion tensor can be used to infer the white matter connectivity of the brain (i.e., tractography; trying to see which part of the brain is connected to which other part).

PRACTICAL CONSIDERATIONS MRI has become a virtually indispensable modality in the field of neurology. As a consequence of the vastly superior contrast resolution of MRI, the CT scan has been largely replaced, except for bone structures and brain calcifications that are not well detected on MRI. MRI is now used as the method of choice to explore the anatomy of the brain in vivo. For children, sedation may be necessary (from 3 months to 5 years). If the children have behavioral disturbances after 5 years of age, general anesthesia can be performed. MRI may confirm a clinical hypothesis or reveal the clinically unsuspected nature and location of a neurological disorder. Judicious modulation of the different methods of imaging requires the radiologist to be guided by precise clinical indications. T1, T2, and FLAIR weighted images are employed on almost all occasions, and additional planes and sequences depend on the clinical problem. The best definition of gray matter structures, especially the cerebral cortex, is obtained with 3D T1 FSPGR. Abnormal signals in the white matter are best seen with T2-weighted images especially using FLAIR. The size of convolutions (pachygyria and microgyria) should be observed, the absence of convolutions (lissencephaly) also. Subcortical or periventricular heterotopia usually can be seen after 3 years of age. For epilepsy, imaging of a frontal lesion requires axial planes in order to see the rolandic region, for temporal anomalies, coronal planes

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perpendicular to the hippocampus are necessary, and sagittal planes are important for midline structures (including vermis of the cerebellum, pituitary stalk, corpus callosum, etc.). Because of the cerebral maturation, the FLAIR sequence is not performed before the age of 1 year. In many instances including epilepsy, MRI should be repeated by the end of maturation at the age of 3 years. Some sequences should be systematically performed where there are specific indications: diffusion-weighted imaging in an acute episode of coma or when stroke is suspected, T2* for dystonia or in case infantile neuroaxonal dystrophy is suspected. MR spectroscopy should be performed in suspected mitochondrial disorders or creatine deficiency. If a lesion is seen on the first MRI sequences, the neuroradiologist at the console may require additional sequences (new voxel spectroscopy for white matter anomalies, T2* for brain cavernoma, etc.). Therefore, brain MRI investigations should be adapted to each given case.

Maturation of myelination The infant’s age must be taken into account because myelination has a different appearance at various stages of development, especially in the first year. At term (40 weeks). On sagittal T1-weighted SE; myelination appears hyperintense. In the anterior colliculus brainstem, the anterior part of the pons is still not myelinated. The corpus callosum is still thin and also unmyelinated. From the basal ganglia, myelinated white matter tracts can be followed toward the rolandic sulcus. Two weeks after birth at term, on T1-weighted images. Myelination is seen in the medulla oblongata, middle cerebellar peduncle, tegmentum pontis, inferior colliculus decussation of the superior cerebellar peduncles, optic tracts, posterior limb of the internal capsule, and ascending tracts toward the rolandic sulcus. On T2-weighted images the tegmentum pontis and mesencephalon are darker than the ventral pons. Myelin can also be seen in the superior vermis, posterior limb of the internal capsule, basal ganglia, and ascending tracts into the rolandic sulcus. 2 months. In the posterior fossa, T2-weighted images show that cerebellar myelination has progressed. The bright ring around the dentate nucleus has disappeared, but the peripheral white matter of the cerebellum is still bright. There is still a difference between the basis pontis and tegmentum pontis. In the mesencephalon, the pyramidal tracts and decussation of the superior cerebellar peduncles can be seen. 3 months. The myelinated structures can easily be identified on T1-weighted images. The optic tract is myelinated, as the optic radiation. The posterior limb of the internal capsule is fully myelinated. Myelin has now spread to the precentral gyrus and will advance dorsally

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and ventrally to myelinate the occipital, frontal, and, finally, the temporal lobes. 4 months of age. On T2-weighted series, the pons, basis, and tegmentum have a low signal as do the middle cerebellar peduncles. The white matter of the cerebellum is myelinated. At the level of the mesencephalon, the decussation of the superior cerebellar peduncles, the inferior colliculus, the pyramidal tracts, and the optic tract have a low signal. The posterior limb of the internal capsule is also dark. A difference is visible between the unmyelinated white matter in the frontal and temporal regions and the occipital and parietal region where myelination has started. 5 6 months. The genu of the corpus callosum starts to myelinate. On T1-weighted images myelination will soon appear to be complete. T2-weighted images will then be more useful in providing information about maturation of the brain. 7–8 months. On the T2-weighted images the central parts are now myelinated, including the genu of the corpus callosum. 12–13 months. The adult contrast is now emerging in all lobes except the temporal lobe, the latest to myelinate. The T2-weighted series shows that the spread of myelin into the arcuate fibers is still not complete. Completion of myelination on T2 is seen at the end of the 2nd year except for the temporal lobe, which finishes myelinating at about 4.5 years old.

PRENATAL AND NEONATAL PERIOD Main imaging abnormalities in the prenatal and neonatal period In most metabolic encephalopathies brain imaging is normal at birth with no marked volumetric change, which may constitute an argument in favor of this class of disorders. In the newborn, there is poor differentiation of gray and white matters, and the gyral pattern can appear simplified – shallow and reduced (because of prematurity for example). MRI may reveal congenital lesions of the white matter, cerebral cortex, basal ganglia, and corpus callosum in some peroxysomal disorders, organic and amino acidopathies which need to be distinguished from the far more frequent ischemic lesions of prenatal or perinatal origin. The main types of brain imaging lesions are as follows:

CYSTIC LESIONS Cystic lesions of the white matter are often initially thought to result from anoxic/ischemic damage. However, they may result from sulfite oxidase deficiency, pyruvate carboxylase deficiency (Fig. 6.1), pyruvate dehydrogenase deficiency, and Zellweger syndrome as well as other peroxysomal diseases (including neonatal refsum and

Fig. 6.1. Pyruvate carboxylase deficiency in a 4-week-old girl. FLAIR coronal section shows slight dilatation of lateral ventricles with bilateral frontal cysts. There was a lactate peak on spectroscopy.

adrenoleukodystrophy). White matter abnormalities (with or without cysts) can also be seen in mitochondrial leukoencephalopathy (especially mutation in nuclear genes of Complex I, including NDUFS1) (Lebre et al., 2010).

GYRAL ANOMALIES Gyral anomalies can be seen in pyruvate dehydrogenase deficiency, peroxysomal disorders (polymicrogyria in Zellweger), and in O-glycosylation disorders as in muscle eye brain disease (Fig. 6.2), Walker Warburg syndrome, Fukuyama disease (type II lissencephaly with white matter and cerebellar anomalies), congenital muscular dystrophy: DMC1-C (fukutin related protein), DMC1-D (LARGE protein); POMGNT1, POMT1, and POMT2. In O-glycosylation disorders the pons and cerebellar vermis are hypoplastic, whereas in anomalies of N-glycosylation such as CDG1A (congenital disorders of glycosylation type 1a), MRI is normal at birth. The irregular inner border indicates a disorganized, polymicrogyric cortex, compatible with lissencephaly type II. The white matter of cerebral hemispheres has an abnormal signal. The cerebellar cortex is also disorganized and there are many small subcortical cysts (Fig. 6.2). The size of the ventricles ranges from normal to markedly dilated. In serine deficiency, gyration may be simplified; in Fumarase deficiency, MRI may show polymicrogyria. Holoprosencephaly may be seen in untreated maternal phenylketonuria (PKU) (Keller et al., 2000) and cholesterol metabolism disease (i.e., Smith Lemli Opitz syndrome). Focal polymicrogyria are associated with submicroscopic chromosomal rearrangements detected by CGH microarray analysis (Quelin et al., 2012).

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Fig. 6.2. Muscle eye brain (MEB) disease of Santavuori in an 8-month-old girl. T2 axial slices show bifrontal polymicrogyria and diffuse supratentorial anomalies of the white matter. There are cortical and subcortical cerebellar cysts, and pontine atrophy.

AGENESIS OF THE CORPUS CALLOSUM Agenetic or very hypoplastic corpus callosum (Fig. 6.3) may result from pyruvate dehydrogenase deficiency and nonketotic hyperglycinemia. Acrocallosal syndrome (ACLS) corpus callosum agenesis or hypoplasia, craniofacial dysmorphism, duplication of the hallux, postaxial polydactyly, and severe mental retardation may be due to mutations in KIF7 (Putoux et al., 2012).

BASAL GANGLIA Basal ganglia may be involved in mitochondrial disorders (Fig. 6.4), organic acidurias (methylmalonic acidemia with pallidum involvement, and propionic acidemia with putamen and caudate involvement; Fig. 6.5) and in pyruvate

Fig. 6.3. Pyruvate dehydrogenase deficiency in a 5-year-old boy. Sagittal T1 slice shows hypoplastic and dysmorphic corpus callosum.

dehydrogenase deficiency, molybdenum cofactor deficiency (sulfite oxidase deficiency), L2 hydroxyglutaric aciduria (globi pallidi and subcortical white matter, cerebellar dentate nuclei), and ethylmalonic aciduria (ETHE1 – with cerebellar signal hyperintensities on T2). Urea cycle defects (OTCD, see Chapter 181). In neonates, neuroimaging shows severe brain edema. MRI shows diffuse cerebral edema and may demonstrate involvement of the basal ganglia with a high signal in the caudate nucleus, putamen, and/or globus pallidus on T2-weighted images and a high signal in the globus pallidus on T1-weighted images. The deep sulci of the insular and perirolandic region may also display high hyperintensity on T1. The basal ganglia are often involved but the thalamus, brainstem, and cerebellum tend to be relatively spared. In this group, the main differential diagnosis is kernicterus (with high signal on T1, Fig. 6.6) and neonatal hypoxic ischemic encephalopathy (with frequent thalamic lesions). SUCLG1 mutations cause encephalomyopathy and mild methylmalonic aciduria (MMA) with bilateral hyperintensities of the caudate nuclei and putamen. MRS shows elevated lactate, decrease of N-acetyl aspartate (NAA) peak. Patients display moderate cortical atrophy, caudate atrophy and ventricular dilatation (Valayannopoulos et al., 2010). Severe encephalomyopathy with choreoathetotic movements, and combined respiratory-chain defects with putaminal and caudate hypersignal and atrophy result from homozygous PNPT1 missense mutations (Vedrenne et al., 2012).

ABNORMAL MYELINATION Abnormal myelin is frequent in inherited disorders of amino acid and organic acid metabolism: MRI may show

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Fig. 6.4. Mitochondriopathy in a 4-month-old girl. Axial and coronal T2 slices show bilateral substantia nigra and periaqueductal hypersignal, and dentate, caudate, putamen, and pallidum nuclei hypersignal. MRS spectroscopy (TE 144) shows lactate peaks.

Fig. 6.6. Kernicterus in a 5-year-old boy. Axial and coronal FLAIR slices show hypersignal of globi pallidi and slight ventricular dilatation.

signal abnormalities in the myelin and basal ganglia. In nonketotic hyperglycinemia and maple syrup urine disease, signal abnormalities affect myelin-containing structures (cerebellum, dorsal brainstem, thalami, globus pallidus, posterior limbs of the internal capsules, and corona radiata). ●

Fig. 6.5. Propionic acidemia in a 6-year-old girl. Axial T2 section shows bilateral hypersignal and slight atrophy of the putamen.

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Maple syrup urine disease. In the acute neonatal period, MRI shows abnormal white matter in the cerebellum, dorsal brainstem, thalami, globus pallidus, posterior limbs of the of internal capsules, and corona radiata (Fig. 6.7). MR spectroscopy may show a peak of lactate. Besides, mild diffuse cerebral white matter edema may be present. Nonketotic hyperglycinemia (NKH). In the neonatal phase, MRI may show abnormalities in signal

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Fig. 6.7. Maple syrup urine disease in an 8-month-old girl. Axial T2 slices show extensive hypersignal of brainstem nuclei, median cerebellar peduncles, periaqueductal gray matter, cerebellum, and dentate nuclei. Extensive hypersignal of the supratentorial white matter, and of both thalami and pallidi.

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intensity in the dorsal pons, midbrain, and posterior limb of the internal capsule. The findings are reminiscent of those seen in maple syrup urine disease but tend to be less prominent. Diffuse brain edema in a comatose neonate with NKH could be observed. 1H spectra show an elevated glycine signal at 3.55 ppm with both short and long echo times. Biotinidase deficiency. MRI shows variable abnormalities including delayed myelination, diffuse cerebral and cerebellar white matter signal abnormality

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and edema, and patchy cerebral and cerebellar white matter abnormalities (Fig. 6.8). White matter abnormalities are partially reversible with treatment. Sufite oxidase deficiency and molybdenum cofactor deficiency. In early postnatal presentation, MRI shows brain edema and extensive areas of abnormal signal, consistent with “hypoxic” changes within the cerebral cortex. Follow-up MRI shows extensive cystic degeneration of the cerebral hemispheres, with large and smaller cysts within the white matter and enlargement

Fig. 6.8. Biotinidase deficiency in a 3-month-old boy. Axial T2 slices show extensive hypersignal of cerebellar white and gray matters, without involvement of the brainstem. Extensive hypersignal of supratentorial white matter and pallidi.

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Fig. 6.9. Menkes disease in a 3-month-old boy. T1 coronal slice shows blood in the right subdural space.

of the ventricles and subarachnoid spaces. The basal ganglia are atrophic and may contain cysts. In case of neonatal leukoenphalopathy with cysts, a vanishing white matter disease or Aicardi Goutie`res syndrome could be suspected in the first line.

LARGE SUBDURAL SPACES Large subdural spaces are seen mainly in Menkes disease (Fig. 6.9) and glutaric aciduria type I. In Menkes disease, brain imaging shows tortuous cerebral arteries and cerebral atrophy with a reduced volume of white matter, which is hypomyelinated. Edematous temporal lesions could mimic herpetic encephalitis. In glutaric aciduria type I, fronto-temporal CSF spaces and sylvian fissures are large, and basal ganglia could be involved (mostly the striatum and uncommonly the pallidum).

AFTER 3 MONTHS OF LIFE In case of clinical suspicion of neurodegenerative or metabolic disorders, specific neurological signs, sensorial deficit (deafness, retinis, optic atrophy), neuropathy, and extraneurological signs (skeletal, cardiac, cutaneous, visceromegaly) are important features to guide the investigations. Visceral, craniovertebral, ocular, or other somatic abnormalities associated with slowing down or regression of development strongly suggest mucopolysaccharidosis. Isolated dystonia can reveal the early-onset form of glutaric aciduria type I or cerebral creatine deficiency. Dystonia associated with abnormal ocular movements can also be

observed as a subtle but revealing sign in X-linked Pelizaeus-Merzbacher syndrome or in MCT8 mutation. Spastic paraplegia and ataxia associated with psychomotor retardation may reveal the cerebral folate deficiency syndrome. Severe psychomotor deterioration including dementia and neurological impairments expressing diffuse central nervous system involvement with pyramidal signs, ataxia, seizures, and visual failure reveals two main groups of disorders: lysosomal and peroxysomal diseases. Late-onset forms of Niemann-Pick type C, Gaucher disease, and GM2 gangliosidosis are suspected because of hepatosplenomegaly, supranuclear paralysis, or macrocephaly respectively. According to age, additional peripheral neuropathy favors a diagnosis of infantile or juvenile Krabbe disease, late infantile or juvenile metachromatic leukodystrophy, and adrenoleukodystrophy, whereas anterior horn dysfunction could indicate infantile neuroaxonal dystrophy. An acute onset preceded by psychomotor delay, short stature, or sensorial deficit (deafness, retinitis) tends to indicate mitochondrial disorders, which can be revealed by various clinical presentations: Leigh syndrome, recurrent ataxia, myoclonic epilepsy, but also progressive neurological deterioration. Predominant epilepsy and myoclonus associated with ataxia and frequent falling may result from infantile ceroid lipofuscinosis. Predominant cerebellar ataxia and ocular movement disorders reveal: Friedreich ataxia (cardiomyopathy, sensitive neuropathy) and other hereditary ataxias (AOA1, AOA2). Associated extraneurological signs contribute to recognizing ab-lipoproteinemia (gastrointestinal) and ataxia telangiectasia (recurrent infections). Extraneurological disorders also indicate peroxisomal disorders including Refsum disease (hepatomegaly) and CDG1A syndrome (cutaneous anomalies and thrombosis or stroke-like). Behavioral disturbances between 5 and 15 years of age may reveal various inborn errors of metabolism, including San Filippo, SSADH (succinic semialdehyde dehydrogenase) deficiency, and Ornithine transcarbamylase (OTC) deficiencies that can present with intermittent abnormal behavior and change in personality and affect until hyperammonemia and coma reveal the cause.

The main imaging abnormalities after 3 months of life BASAL GANGLIA: SUBCORTICAL GRAY STRUCTURES Hyperintensity on T2 and FLAIR sequences Signal anomalies of basal ganglia in metabolic encephalopathies include striatal lesions seen in Leigh syndrome, related mitochondrial encephalopathies and Leber disease, etc., familial striatal necrosis (nup62), biotine responsive

CLINICAL AND IMAGING DIAGNOSIS FOR HEREDODEGENERATIVE DISEASES basal ganglia disease (SLC19A3), SUCLa2, and SUGLg1, Pyruvate dehydrogenase deficiency (PDH), Glutaric aciduria type 1 (open opercula and free space anterior to the temporal lobe with striatal signal abnormalities; Fig. 6.10), L2 hydroxyglutaric aciduria (with extensive white matter anomalies affecting U fibers and anomalies of the globi pallidi), thiamine deficiency, organic amino aciduria, methylmalonic aciduria (pallidum), propionic acidemia (putamen and sometimes pallidum and caudate), GM1 or GM2 gangliosidosis (slight hyperintensity of the basal ganglia on T2 with hypomyelination) (Fig. 6.11). Hypointensity on T2 In cerebrotendinous disease. The globus pallidus has a low signal on T2. The pyramidal tracts in the brainstem, the medial lemniscus at the level of the pons, the cerebellar hemispheric white matter, and the hilus of the dentate nucleus display elevated signal intensity. The dentate nucleus stands out as dark. In Wilson disease thalami, putamen and caudate as brainstem and cerebellar white matter present a high signal

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on T2, whereas the globus pallidus has a high signal on T1 and T2. Dentate nuclei may also exhibit low signal on T2. Atrophy of the caudate nucleus is an early sign in Wilson disease and Huntington disease (Fig. 6.12). Hypointensity on T2* of basal ganglia indicates iron accumulation. Neurodegeneration with brain iron accumulation is produced by de novo mutations with somatic mosaicism in surviving males and germline or somatic mutations in females in WDR45 determine early-onset global developmental delay and further neurological deterioration (parkinsonism, dystonia, and dementia developing by early adulthood) with iron deposition in the substantia nigra and globus pallidus (Haack et al., 2012). Pantothenate kinase-associated neurodegeneration Pantothenate kinase-associated neurodegeneration (PKAN) is caused by mutations in pantothenate kinase2 (PANK2). The T2* sequence shows characteristic changes due to the accumulation of iron in the globus pallidus and to a lesser extent later in disease, the substantia nigra. The so-called “eye-of-the-tiger” (EoT) sign is virtually pathognomonic of this disorder. Neuroaxonal dystrophy

Fig. 6.10. Glutaric aciduria type II in a 2-year-old boy. Axial T2 slices show bitemporal and bisylvian effusion with bilateral brainstem signal anomalies. Supratentorial hypersignal of putamen, pallidum, and thalami, with hypersignal of the white matter.

Mutations in the gene encoding calcium-independent phospholipase A2 (PLA2G6) lead to neuroaxonal dystrophy (NAD) which is subdivided into an infantile form (INAD) (Fig. 6.13) and later-onset, atypical forms. NAD often features iron deposition in the globus pallidus. The substantia nigra may also be affected. Significant atrophy of both the cerebellar vermis and hemispheres is a frequent feature and typically precedes iron accumulation. Confluent T2 white matter hyperintensities may be observed. Neuroferritinopathy Neuroimaging may demonstrate high T2 signal in the basal ganglia early in the course of neuroferritinopathy (NFT). In general, excess iron deposition becomes evident in the putamen, globus pallidus, and dentate nucleus. The caudate and thalamus may also be involved. Aceruloplasminemia In aceruloplasminemia (ACP) MRI reveals involvement of the caudate, putamen, globus pallidus, thalamus, red nucleus, and dentate. Cerebellar atrophy may also occur.

Fig. 6.11. GM2 gangliosidosis in a 17-month-old boy. Axial FLAIR (A) and T2 (B) slices show abnormal myelination of cerebellar white matter. In subtentorial areas, hypersignal of putamen, pallidum and caudate, and hyposignal of thalami. The myelin is extensively abnormal.

Fatty acid hydroxylase-associated neurodegeneration Neuroimaging features of fatty acid hydroxylaseassociated neurodegeneration (FAHN) include the characteristic presence of iron in the globus pallidus. The

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Fig. 6.12. Huntington disease in a 15-year-old boy. Axial T2 (A and B) and T1 (C) slices show hypersignal and atrophy of putamen and caudate, and dilatation of frontal horns.

Aicardi Goutie`res syndrome, Cockayne, MELAS, or AP1S2 gene mutations, for example. In Aicardi Goutie`res syndrome MRI discloses progressive brain atrophy with white matter abnormalities. In Cockayne syndrome, associated severe white matter abnormalities and posterior fossa hypoplasia/atrophy are seen. In MELAS, stroke-like images could also be associated with cerebellar atrophy.

CEREBRAL WHITE MATTER Fig. 6.13. INAD in a 6-year-old boy. Coronal FLAIR (A) and axial T2* (B) slices show hypersignal and atrophy of cerebellar cortex with hypersignal of the dentate nucleus, with white matter signal anomalies. Iron is accumulated in both pallidi (B).

substantia nigra may be affected to a lesser degree. Other features include confluent subcortical and periventricular white matter T2 hyperintensities along with thinning of the corpus callosum. Cerebellar and brainstem atrophy worsen with time and may be profound. Calcification of the basal ganglia Intracerebral calcifications (Fig. 6.14) were an uncommon radiographic finding prior to the advent of CT, which is a more sensitive detector of calcifications than MRI. Brain calcifications can result from various injuries (infection, radiotherapy, chemotherapy etc.). They tend to concentrate in the basal ganglia but can also accumulate within the cerebral cortex, around the ventricles and within tumors. Calcifications can be symptomatic of various causes and classifications can be proposed based on the distribution (unilateral/bilateral) and location (cerebral cortex, meningeal, periventricular, parenchymal, and basal ganglia). The clinical signs and the evolution of the disease (chronic or stable) will also guide the complementary explorations (lumbar puncture, MRI and 1MRspectroscopy, skin biopsy, phosphocalcic test, antinuclear antibodies, etc.). Calcifications are helpful to diagnose

The detection of abnormalities in the cerebral white matter is one of the major contributions of MRI. The characteristic signal (on T1 and T2 and FLAIR weighted images) given by myelin on MRI makes it possible to appreciate the level of myelination in young infants and evaluate degrees of myelination delay. For white matter diseases, predominating topography (anterior, posterior) of abnormalities is determined by systematic and detailed inspection of periventricular, subcortical (U fibers), corpus callosum, pyramidal tract, and posterior fossa. A reduced amount of myelin may reflect failure in myelin development. Three types of consequences may occur: dysmyelination (formation of abnormal myelin), demyelination (destruction of myelin), and hypomyelination (failure to form myelin primary metabolic disturbance in the synthesis of a myelin protein). Progressive diffuse brain atrophy in West syndrome with marked hypomyelination may be due to SPTAN1 gene mutation (Nonoda et al., 2013). In the group of genetic leukodystrophies (nonacquired myelin disorder), the main pathologies are: 1.

2.

Defect in the synthesis of a myelin protein: Pelizeaus Merzbacher disease (Fig. 6.15) and thyroid hormone transposter defect (MCT8). In galactosemia type 1, T2-weighted images show a combination of hypomyelination and patchy high signal intensity white matter abnormalities. Lysosomal diseases such as etachromatic leukodystrophy, Krabbe diseases (Fig. 6.16), mucopolysaccharidosis (Fig. 6.17), gangliosidosis (GM1 and GM2) (Fig. 6.11), neuronal ceroid lipofuscinosis. Severe

CLINICAL AND IMAGING DIAGNOSIS FOR HEREDODEGENERATIVE DISEASES

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Unilateral Parenchyma

Cortex

Meningeal

Periventricular

Tumors Crariopharyngioma Pineablastoma Ependymoma PNET Oligodendroglioma Teratoma

Epileptogeric lesions DNET, dysplasia Ganglioglioma Vascular malformation Cavernoma Cysticercosis Hemimegalencephaly Traumatism, hematoma, shaken baby sd

Sturge-Weber Iatrogeric Meningioma

Tuberous sclerosis, Covernoma

Bilateral

Asymmetric

Symmetric Stable disease

Periventricular basal ganglia Ê parenchyma Infections TORCH Taxoplasmosis, CMV, Herpes simplex, rubella Tuberculosis Parasitic HIV Tuberous sclerosis

Basal ganglia Ê Parenchyma Hypoxia Birth anoxia, Cardiovascular event Toxins (carbon monoxide etc..) Down syndrome

Chronic disease Basal ganglia

Basal ganglia ± Parenchyma

Cockayne syndrome Mitochondrial disorder (MELAS, MERRF, Kearn-sayre) Aicardi-Goutieres syndrome Metabolic diseases AP1S2 gene PKAN, Fabry, Biotinidase, Folates, krabbe, osteopetrosis dysparathyroidism, oxydase Sulfitis, Tay-Sadis <> Systemic lupus Radiation, chemotherapy

Fig. 6.14. Algorithm for brain calcifications.

Fig. 6.15. Pelizaeus–Merzbacher in a 5-year-old boy. Axial T2 (A B) and T1 (C E) slices show extensive subtentorial hypomyelinization. Myelination of rolandic semiovale and posterior arm of capsules corresponds to that of a 3-month-old child in T1.

3. 4.

cortical and cerebellar atrophy suggests first neuronal ceroid lipofuscinoses or gangliosidosis. Peroxisomal disorders such as X-linked adrenoleukodystrophy and Refsum disease. Mitochondrial dysfunction (with Leigh encephalopathy, complexes I, II, IV (Cox10), traduction deficiency, MNGIE, Kearns Sayre, pyruvate carboxylase deficiency, etc.). In these diseases, basal ganglia, brainstem, and cerebellum are often involved in addition to leukoencephalopathy. Thus,

MRI expression of mitochondrial ND5 mutations mimick brainstem tectal glioma (Rio et al., 2010). Progressive nystagmus, cerebellar ataxia, pyramidal signs, and slurred speech since toddlerhood with hyperintensity of the cerebellum, the anterior brainstem, and the pyramidal tract, sparing the pontine tegmentum on T2 MRI, and lack of cerebellar NAA and choline on proton magnetic resonance spectroscopy is caused by NUBPL mutations (Tenisch et al., 2012).

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Fig. 6.16. Krabbe disease in an 11-month-old boy. Coronal FLAIR slice shows cerebellar and and dentate nuclei hypersignal, and subtentorial periventricular hypersignal.

Fig. 6.17. Mucopolysaccharidosis in a 4-year-old boy. Sagittal T1 and axial T2 slices show dilated Wirschow Robin spaces in the periventricular white matter, corpus callosum, and thalami.

5.

6.

Disorders of amino acid and organic acid metabolism: glutaric aciduria type 1, propionic academia, Maple syrup disease, Canavan, L2 hydroxyglutaric aciduria. In these diseases, basal ganglia and cerebellum are also often involved with the leukoencephalopathy. Miscellaneous: Alexander disease and megalencephalic leukoencephalopathy with cysts cause macrocephaly. Vanishing white matter (CACH) should also be considered (Fig. 6.18).

Periventricular white matter anomalies. Bilateral and symmetrical signal abnormalities of the periventricular white matter involvement is seen in adrenoleukodystrophy, metachromatic leukodystrophy, Krabbe disease, muscular dystrophy due to merosin deficiency (including U-fibers), and also mitochondrial cytopathies (MNGIE for example with variable U fibers involvement). Hyperdensity of the basal ganglia (especially the thalami) with

Fig. 6.18. Vanishing white matter in a 22-month-old boy. Axial T2 and coronal FLAIR slices show extensive periventricular white matter anomalies with parieto-frontal cavitations.

involvement of pyramidal tract and cerebellar white matter suggest Krabbe disease. The posterior part of the periventricular white matter is affected at the earliest stages of metachromatic leukodystrophy and adrenoleukodystrophy. Furthermore, early sparing of U-fibers with tigroid aspect of the periventricular white matter is characteristic of metachromatic leukodystrophy. T2-weighted and FLAIR sequences show diffuse high-signal intensity of cerebral and cerebellar white matter, and usual but not invariable sparing of the U fibers and the corpus callosum are features of MNGIE. The thalami and basal ganglia may display patchy signal abnormalities. The internal capsule, external capsule, brainstem, and middle cerebellar peduncles may be involved as well. In some patients the white matter abnormalities are more limited and most prominently involve the periventricular white matter. Subcortical white matter anomalies are mainly seen in Alexander disease, Canavan disease (with pallidal involvement), CACH (vanishing white matter disease), mitochondrial cytopathies, ribose-5-phosphate isomerase deficiency (polyols deficiency), and megalencephalic leukoencephalopathy with subcortical cysts (MLC1 gene). In mutations of MLC1 the cerebral hemispheric white matter is diffusely abnormal and edematous. The edema is most marked during the first years of life, with obliteration of peripheral CSF spaces and narrowing of the ventricles. Sparing of the corpus callosum and the presence of a double line of high signal involving the posterior limb of the internal capsule are frequently seen. The external and extreme capsules are prominently involved. The central white matter structures, including the corpus callosum, anterior limb of the internal

CLINICAL AND IMAGING DIAGNOSIS FOR HEREDODEGENERATIVE DISEASES capsule, posterior limb of the internal capsule, and a periventricular rim of occipital white matter are relatively spared. There are mild signal abnormalities in the cerebellar white matter. Cystic lesions involve the anterior temporal and frontal regions. Extensive brain white matter abnormalities, most pronounced in the subcortical area with some swelling of the abnormal white matter is characteristic of ribose5-phosphate isomerase deficiency. 1H-MRS of the brain reveals highly elevated peaks between 3.6 and 3.8 ppm (Huck et al., 2004). Abnormal contrast enhancement after gadolinium injection is characteristic of Alexander disease (that could mimic a tumor) and adrenoleukodystrophy (posterior bilateral white matter abnormalities and corpus callosum involvement). In adrenoleukodystrophy, the abnormalities could also involve the pyramidal tracts. Increased head circumference with white matter hyperintensity occurs in Canavan disease, Alexander disease (with anterior anomalies), glutaric aciduria type I, mucopolysaccharidosis, and megalencephalic leukoencephalopathy with subcortical cysts (MLC1 gene). White matter anomalies predominant on pyramidal tracts suggest Krabbe disease, mitochondrial cytopathies (DARS2 gene) (Scheper et al., 2007), late-onset adrenoleukodystrophy, or cerebrotendinous xanthomatosis. White matter involvement with basal ganglia anomalies should indicate first mitochondrial chain deficiency (included Kearns Sayre disease with no respect of U-fibers, sparing of periventricular white matter), including Leigh encephalopathy with complexes I, II, IV (Cox10) deficiencies, translation deficiency, or MNGIE. In mitochondrial chain deficiency, white matter anomalies could involve the pyramidal tract as in DARS 2 (translation deficiency) associated with signal abnormalities of the spinal cord. White matter involvement with basal ganglia anomalies could also be seen in pyruvate carboxylase deficiency, cerebrotendinous xanthomatosis, Canavan disease, Alexander disease, Wilson disease, Aicardi Goutie`res disease, L2 hydroxyglutaric aciduria, and gangliosidoses (GM1 and GM2). In L2 hydroxyglutaric aciduria, subcortical white matter is involved whereas the central white matter is spared including the corpus callosum; subcortical lesions are partly multifocal, partly confluent. Lesions are present in central gray matter structures, most prominently the globus pallidus and dentate nucleus. In Cockayne syndrome, the associated posterior fossa hypoplasia and calcifications of the basal ganglia are characteristic. White matter abnormalities with cysts are observed in CACH disease (childhood ataxia with central hypomyelination syndrome; Fig. 6.18), also called leukoencephalopathy with vanishing white matter, in MLC1 gene mutation, in sulfite oxidase deficiency, in RNASET2 deficiency in

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Fig. 6.19. Ito syndrome in a 9-year-old boy. Axial T2 (A) and FLAIR (B) slices show dilated subcortical Wirschow-Robin spaces, mainly in the posterior aspect of both hemispheres. In addition, there are posterior periventricular heterotopia (A).

which cystic leukoencephalopathy resembles congenital cytomegalovirus brain infection, and Aicardi-Goutie`res disease. Extensive white matter lesions also may occur in Cockayne (with calcifications), Sj€ogren Larson and Zellweger (with posterior fossa and gyral anomalies) syndromes. In mitochondrial cytopathy, a major cystic leukoencephalopathy could also be seen (Lebre et al., 2010). White matter abnormalities with very small cysts. The MRI pattern of multifocal, irregular, patchy white matter abnormalities with small cysts and enlarged perivascular (Wirchow Robin) spaces is observed in LOWE syndrome, hypomelanosis of Ito (Fig. 6.19), and some mucopolysaccharidoses and late stage of maple syrup urine disease. Hypomyelination In the group of primary metabolic disturbance of a myelin protein synthesis (hypomyelination), the main pathologies are Pelizaeus Merzbacher disease (Fig. 6.15) and Thyroid hormone transporter (MCT8) (Pelizaeus Merzbacherlike disease presentation of MCT8 mutated male subjects), connexine 46.6 (GJA12 gene) (Wibom et al., 2009), hyccin deficiency (hypomyelination with cataract) (Zara et al., 2006), and AGC1 gene mutation (Wibom et al., 2009). The main differential diagnoses are the 18q deletion (Fig. 6.20) and Cockayne syndrome. In 18q syndrome, MR images show a variable myelin deficit. Initially, myelination is delayed but improves on each followup MRI. In older patients a stable picture of incomplete myelination is seen. The severity of the myelin deficit is variable. In some patients, a near-total absence of myelin in cerebral and cerebellar white matter, internal capsule, and corticospinal tracts is seen with relatively normal myelination of the corpus callosum. Partial hypomyelination often produces poor differentiation between white and gray matters. The myelin deficiency in the cerebral hemispheric white matter is often patchy with focal white matter signal abnormalities.

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N. BODDAERT ET AL. MELAS syndrome and respiratory chain deficiency (especially Complex I with mitochondrial mutation of the POLG gene), and b-oxidation defects. Stroke episodes can be seen in hyperhomocysteinemias. Tortuous arteries are characteristic of Menkes disease.

ATROPHY OF THE CEREBRAL CORTEX

Fig. 6.20. 18q mosaic in a 27-year-old girl. Axial T2 and coronal FLAIR slices show hypersignal of the white matter that is patchy and confluent on both sides.

Involvement of the white matter associated with hypoplasia of the posterior fossa and basal ganglia calcifications is a characteristic of Cockayne disease. MR spectroscopy and leukoencephalopathy/ abnormal MRI MRS findings reflect neuronal loss and increased cellular turnover of choline and myoinositol are increased whereas NAA (N-acetyl aspartic acid) is decreased in Alexander, adrenoleukodystrophy, and Krabbe diseases. Canavan disease has a significant increase in NAA. Increased lactate levels could be seen in mitochondrial disorders, some recently identified, such as DARS2, pyruvate carboxylase deficiency, glutaric aciduria type I, and maple syrup disease. Generally no lactate is present in Alexander, MLC1, adrenoleukodystrophy or Canavan diseases. 1H spectra show an elevated glycine signal at 3.55 ppm on both short and long echo times in nonketotic hyperglycinemia. Elevated succinate, represented by a resonance at 2.40 ppm, can be found in some patients with succinate dehydrogenase deficiency, a mitochondrial disorder with a defect in complex II (Brockmann et al., 2002). A prominent singlet is found at 1.3 ppm, the lipid region of the spectrum in Sj€ ogren–Larsson syndrome. The peak is seen with both short and long echo times. These findings are compatible with the presence of an abnormal amount of lipids. The peaks are only found in the cerebral white signal abnormalities and not in the cerebral gray matter or cerebellum (Willemsen et al., 2004). Highly elevated levels of the polyols D-arabitola and ribitol are found at 3.6 to 3.8 ppm with white matter proton magnetic resonance spectroscopy in ribose5-phosphate isomerase deficiency (Huck et al., 2004).

VASCULAR DISORDERS Stroke-like episodes. Strokes that are not confined to arterial vascular territories affect CDG1A, urea cycle defect (OTCD: ornithine transcarbamylase deficiency),

Global cortical atrophy is a frequent feature in the course of most heredodegenerative disorders. Severe isolated cortical atrophy associated with cerebellar atrophy suggests first lysosomal disorders (neuronal ceroid lipofuscinoses, gangliosidosis GM1 and GM2, Niemann Pick type C, and some mitochondrial dysfunctions: Alpers, MELAS, translation deficiencies (Edvardson et al., 2007)).

BRAINSTEM Pontocerebellar hypoplasia These heterogeneous disorders include children with very similar clinical presentation characterized by microcephaly associated with severe mental retardation, extrapyramidal signs with movement disorders, and visual impairment. All pontocerebellar hypoplasias are really neurodegenerative diseases beginning in fetal life, so that hypoplasia and progressive atrophy of the cerebellum and also the cerebral cortex and hippocampus occur concurrently. The clinically best defined forms either predominate with motor neuron involvement and resemble infantile spinal muscular atrophy or present without motor neuron disease but with dyskinesias preceding cerebellar and corticospinal tract deficits (Sarnat, 2001). Patients have mutations mainly in TSEN54, but also in TSEN2, TSEN34, and CASK genes, as recently reported. Mutations of TSEN and CASK genes are prevalent in pontocerebellar hypoplasias type 2 and 4 (Valayannopoulos et al., 2012). Massive and exclusive pontocerebellar damage is due to NUBPL mutations (Tenisch et al., 2012). Abnormal dorsal brainstem associated with cerebellar hypoplasia These children present with clinical signs of cranial nerve dysfunction, particularly anesthesia of the trigeminal nerve territory. They have pyramidal signs, dysmetria, trunk ataxia, and mild mental retardation with a normal head circumference. The asymmetrical involvement of cranial nerves (VII, VIII, VI, and V) seems to be specific and is called pontine tegmental cap dysplasia (Fig. 6.21) (Barth et al., 2007). Signal abnormalities in the brainstem involve Leigh syndrome (especially Complex 1, Surf1 or NARP) and RANPB2 (Neilson et al., 2009) (Fig. 6.22). Thiamine deficiency (Wernicke encephalopathy) causes bilateral anomalies in the brainstem and thalami.

CLINICAL AND IMAGING DIAGNOSIS FOR HEREDODEGENERATIVE DISEASES

Fig. 6.21. Pontine tegmental cap dysplasia in a 9-year-old girl. Sagittal T1 and axial T2 shows that the pons is hypoand dysplastic in its posterior aspect. Major cerebellar atrophy with dilatation of the fourth ventricle.

CEREBELLUM Progressive cerebellar atrophy as an isolated or predominant morphological abnormality may be seen in a variety of metabolic or degenerative disorders and is an important diagnostic clue in some conditions (Boddaert et al., 2010), such as CDG1A (Fig. 6.23), late-onset GM2 gangliosidosis (with slight hyperintensities of the basal ganglia and T2 hypointensity of the thalami), some SCAs, early infantile neuroaxonal dystrophy, mitochondriopathy such as quinone deficiency (Coq8) or POLG mutation, and infantile neuroaxonal dystrophy (INAD) with two mutations in the PLA2G6 gene. In CDG1A, the cerebellum is normal at birth, and atrophy appears progressively within the first year of life; no correlation was observed between the degree of cerebellar atrophy and the severity of mental retardation. Ocular apraxia associated with ataxia and negative MRI may result from AOA1 or AOA2 gene mutations. Delayed atrophy is also seen in ceroid lipofuscinosis (with supra-tentorial atrophy), ataxia telangiectasia, and cholesterol metabolism abnormality (Smith Lemli Opitz syndrome). Infantile Ravine encephalopathy including anorexia with irrepressible and repeated vomiting with severe failure to thrive, acute brainstem dysfunction with progressive and severe vanishing of the cerebellar white matter and brainstem atrophy, as well as sus-tentorial periventricular white-matter hyperintensities associated with basal ganglia anomalies, is due to mutation in a primate-conserved retrotransposon reveals a noncoding RNA (Cartault et al., 2012).

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Fig. 6.23. Congenital glycosylation deficiency in a 5-year-old boy. Sagittal T1 shows major atrophy of cerebellar vermis (A) and hemispheres (B) with mild atrophy of brainstem contrasting with normal supratentorial structures.

In case of an associated optic atrophy with cerebellar atrophy, mitochondrial disorders (OPA1) and spastic paraplegia (SPG7) should be investigated. In Friedreich ataxia MRI is normal in childhood but iron quantification with T2* shows iron in the dentate nuclei (Boddaert et al., 2007). Signal abnormalities in the cerebellum could result from cerebrotendinous xanthomatosis, L2 hydroxyglutaric aciduria, semialdehyde succinate dehydrogenase, Sj€ogren Larsson, sulfite oxidase deficiency, mitochondrial disorders as mutations in the twinkle gene, Wilson disease, and late-onset peroxysomal disorders. In Wilson disease, the pallidum and also putamen may have a low signal on T2 as well as the dentate nuclei. Cerebellar spectroscopy is useful to search for lactate peaks in the posterior fossa in patients with a suspected energy metabolism defect (Boddaert et al., 2008).

MR SPECTROSCOPY WITH NORMAL MRI A severe reduction of the creatine peak in 1H-MRS spectra of the brain is a central feature of so-called creatine deficiency syndromes. Lack of creatine in the brain can be caused by a defect of creatine synthesis due to either guanidinoacetate methyltransferase (GAMT) deficiency or glycine amidinotransferase (AGAT) deficiency,

Fig. 6.22. 5-year-old girl with RANBP2 mutation. Axial T2 slices show major hypersignal of the brainstem that is increased in size. Characteristic bithalamic and bilateral insular hypersignal.

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which both have autosomal recessive inheritance, or by a defect in the transport of creatine across the blood–brain barrier (X-linked creatine transporter defect due to SLC6A8 gene mutation). In ornithine delta-aminotransferase (OAT) deficiency, cerebral proton magnetic resonance spectroscopy revealed a striking creatine deficiency in all patients (Boddaert et al., 2008).

CONCLUSION MRI in unexplained neurological diseases requires T1, T2 and FLAIR and MR spectroscopy. Acute neurological symptoms require an additional diffusion sequence. This may disclose a characteristic MRI pattern, a specific diagnosis even if the clinical picture is atypical, which is the case in patients with late-onset Leigh syndrome, Krabbe, or metachromatic leukodystrophies, PKAN, INAD, Cockayne, etc. MRI may reveal typical alterations of the brain at the preclinical stage. MRI thus is an indispensable tool in the exploration of neurological diseases, including neurometabolic disorders.

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