Neuronal Disease

combined with hypomyelination, dysmyelination, or demyelination. In addition, the peroxisomal disorders tend to affect the posterior limb of the internal capsule, cerebellar white matter, and brainstem tracts. When the cerebral hemispheres are affected, the occipital white matter may be more severely involved posteriorly. Careful inspection of the subcortical U fibers, gray matter, and the splenium of the corpus callosum may help differentiate this pattern in peroxisomal disorders from other conditions such as occipital region infarction or the mitochondrial encephalomyelopathies. The peroxisomal disorders spare the subcortical U fibers and gray matter and preferentially involve the splenium of the corpus callosum. The mitochondrial encephalomyelopathies show combined involvement of deep gray matter nuclei and peripheral white matter.19,328 Other conditions causing primarily cortical gray matter disease early on include the mucopolysaccharidoses (MPS) and lipid storage disorders.

The differential diagnosis of deep gray matter involvement depends on which nuclei are principally involved. The thalamus is involved early in Krabbe disease and also in the GM2 gangliosidoses. Globus pallidus involvement is seen in Canavan disease, Kearns–Sayre syndrome (KSS), methylmalonic and propionic acidemia, and maple syrup urine disease.17 Involvement of the putamen and caudate (striatal disease) is compatible with Leigh disease; (MELAS)

syndrome; and Wilson disease. Hypointensity of the globus pallidus on T2-weighted MR imaging suggests the diagnosis of Hallervorden–Spatz disease.17

Neuronal Disease

Neuronal Ceroid Lipofuscinosis

The neuronal ceroid lipofuscinoses (NCLs) are a group of disorders with common features, but with enough distinctions to warrant subclassification. The NCLs are inherited in an autosomal recessive manner with the exception of the adult form, which may be dominant or recessive.

The overall incidence is estimated at 1 in 100,000 births, but is approximately ten times higher in the Scandinavian population.342 All forms of NCL eventually manifest in intellectual and gross motor deterioration, seizures, and visual loss from retinal degeneration and optic atrophy with an abnormal ERG (Fig. 10.1). Neuroimaging reveals evidence of combined white and gray matter atrophy that is most pronounced in the cerebral hemispheres and the brainstem (Fig. 10.2).257,320 Cardiac problems are common, especially in the late stage of the disease.154 Several lines

of evidence point to functions for the CLN genes in the endosomal–lysosomal system and suggest neuron-specific roles for these proteins.69

Current classification of the NCLs distinguishes eight different disorders, which often encompass clinical heterogeneity.127

Six genes, PPT1, TPP1, CLN3, CLN5, CLN6, and CLN8, are known to be associated with NCL. Two genes, CLN1 and

CLN2, encode for lysosomal proteases palmitoyl protein thioesterase 1 (PPT1) and tripeptidyl peptidase 1 (TPP1), respectively.125 Lysosomal membrane proteins of currently unknown function are encoded for by CLN3, CLN5, CLN6, and CLN8. Most cases of juvenile-onset NCL are caused by mutations in CLN3, which maps to chromosome 16p21.161 The most common is a 1.02 kb deletion that is present on

Fig. 10.2  Neuronal ceroid lipofuscinosis. T1-weighted MR image shows diffuse atrophy of cortical gray matter combined with diffuse thinning of cerebral white matter. Hypointense area is seen in occipital lobe, possibly representing lipofuscin storage material (arrow)

approximately 85% of disease chromosomes.216 Juvenile phenotypes have also been observed following mutations in the CLN1 and CLN2 genes.127 The primary biochemical defect in these disorders is yet to be ascertained, and there is no treatment available.65

The diagnosis of an NCL is often based on assay of enzyme activity and/or molecular genetic testing and, in some instances, on clinical findings and electron microscopy of biopsied tissues as discussed below.27,352 The diagnostic testing strategy in a proband depends on the age of onset. The clinical subtypes correlate with particular mutations and their corresponding enzymatic defects. Two lysosomal enzymes, palmitoyl-protein thioesterase 1 (PPT1), which is encoded by the gene PPT1, and tripeptidyl-peptidase 1 (TPP- 1), which is encoded by the gene TPP1, have been identified as deficient in the neuronal ceroid-lipofuscinosis in white blood cells, fibroblasts, and chorionic villi. Assays of the enzymatic activity of PPT1 and TPP-1 are clinically available. Molecular genetic testing of the PPT1, CLN3, CLN5, CLN6, and CLN8 genes is available on a clinical basis.352

Infantile NCL (Santavuori-Haltia Disease)

Neurological deterioration with severe visual loss occurs between 8 months and 1½ years.273 Intellectual and gross motor

skills are severely affected, myoclonic seizures develop, and death occurs by 4 years of age. The ERG is of low amplitude and ultimately becomes flat,142 reflecting severe retinal degeneration. Cataracts may also be seen in this condition.22 Optic atrophy ensues with progression of disease. CLN1 on chromosome 11p32, encoding PPT1, is the gene most often mutated in this subtype.

Late Infantile (Jansky–Bielschowsky Disease)

These children undergo a similar pattern of deterioration as those with the infantile form, but they gain more skills by the time of onset (age 2–4 years), which makes the degenerative aspect of the disease more apparent. The retinal degeneration is most visible in the macula, but the entire retina is involved as reflected by extinction of the ERG early in the disease.153 CLN2 on chromosome 11p15, encoding TPP1, is the gene most often mutated in this subtype.

Juvenile NCL (Batten Disease)

Visual complaints may be the presenting feature of this disease, occurring between 4 and 10 years of age.292 “Overlooking” is a common behavior in children with NCL.311 The child demonstrating this phenomenon appears to look over the top of the object of regard. This strategy has been noted in children with loss of central vision from damage to the papulomacular bundle.130 Early in the course of the disease, retinal abnormalities may be limited to a striking attenuation of retinal arterioles. As the disease progresses, optic atrophy becomes evident and macular abnormalities develop, including a subtle discoloration and rippling of the internal limiting membrane (Fig. 10.1). A coarse pigment granularity or bull’s-eye maculopathy may also develop. At first, the b wave of the ERG is selectively attenuated, but progression of the disease leads to extinction of both the a and the b waves. The VEP becomes increasingly abnormal as optic atrophy ensues. The CLN3 mutation is most commonly present in this subtype, but molecular genetic testing of PPT1 should be performed if a CLN3 mutation is not found.

Visual problems are usually the presenting symptom. By the time these children come to medical attention, visual acuity is often 20/400 or less. Curiously, these children do not generally complain of difficulty seeing despite the fact that they have not yet developed dementia. Over time, they develop seizures and Parkinsonism, with dysarthria and slow speech. Angry outbursts and depression are common. Myoclonus is seem mainly in other forms of NCL.2a

The following case description illustrates the evolution of visual and neurological dysfunction in juvenile NCL. A boy had a normal prenatal and neonatal course. He walked at 8–9