Because vision loss is often an early sign,<unk>  may be first suspected during an eye exam. An eye doctor can detect a loss of cells within the eye that occurs in the three childhood forms of<unk> . However, because such cell loss occurs in other eye diseases, the disorder cannot be diagnosed by this sign alone. Often, an eye specialist or other physician who suspects<unk>  may refer the child to a neurologist, a doctor who specializes in disease of the brain and nervous system. To diagnose<unk> , the neurologist needs the patient's medical history and information from various laboratory tests. Diagnostic tests used for<unk> s include: * Skin or tissue sampling: The doctor can examine a small piece of tissue under a microscope to spot typical<unk>  deposits. These deposits are found in many different tissues, including skin, muscle, conjunctiva, rectal and others. Blood can also be used. These deposits take on characteristic shapes, depending on the variant under which they are said to occur: granular osmophilic deposits (GRODs) are generally characteristic of INCL, while curvilinear profiles, fingerprint profiles, and mixed-type inclusions are typically found in LINCL, JNCL, and ANCL, respectively. * Electroencephalogram or EEG: An EEG uses special patches placed on the scalp to record electrical currents inside the brain. This helps doctors see telltale patterns in the brain's electrical activity that suggest a patient has seizures. * Electrical studies of the eyes: These tests, which include visual-evoked responses and electroretinograms, can detect various eye problems common in childhood<unk> s. * Brain scans: Imaging can help doctors look for changes in the brain's appearance. The most commonly used imaging technique is computed tomography (CT), which uses x-rays and a computer to create a sophisticated picture of the brain's tissues and structures. A CT scan may reveal brain areas that are decaying in<unk>  patients. An increasingly common tool is magnetic resonance imaging, which uses a combination of magnetic fields and radio waves, instead of radiation, to create a picture of the brain. * Enzyme assay: A recent development in diagnosis of<unk>  is the use of enzyme assays that look for specific missing lysosomal enzymes for infantile and late infantile versions only. This is a quick and easy diagnostic test. Types The older classification of<unk>  divided the condition into four types (CLN1, CLN2, CLN3, and CLN4) based upon age of onset, while newer classifications divide it by the associated gene. CLN4 (unlike CLN1, CLN2, and CLN3) has not been mapped to a specific gene. Type Description OMIM Gene Type 1 Infantile<unk>  (Santavuori–Haltia disease, INCL): begins between about 6 months and 2 years of age and progresses rapidly. Affected children fail to thrive and have abnormally small heads (microcephaly). Also typical are short, sharp muscle contractions called myoclonic jerks. Initial signs of this disorder include delayed psychomotor development with progressive deterioration, other motor disorders, or seizures. The infantile form has the most rapid progression and children live into their mid-childhood years. The gene responsible for infantile<unk>  has been identified in some cases of juvenile/adult onset. These patients are thought to have some partial enzyme production that leads to a protracted, less severe disease course. PPT1 Type 2 Late infantile<unk>  (Jansky–Bielschowsky disease, LINCL) begins between ages 2 and 4. The typical early signs are loss of muscle coordination (ataxia) and seizures, along with progressive mental deterioration, though afflicted children may show mild to severe delays in speech development well before other symptoms appear. This form progresses rapidly and ends in death between ages 8 and 12. TPP1 Type 3 Juvenile<unk>  (Batten disease, JNCL) begins between the ages of 5 and 8 years of age. The typical early signs are progressive vision loss, seizures, ataxia, or clumsiness. This form progresses less rapidly and ends in death in the late teens or early 20s, although some have been known to live into their 30s. CLN3 Type 4 Adult<unk>  (Kufs disease, ANCL) generally begins before the age of 40, causes milder symptoms that progress slowly, and does not cause blindness. Although age of death is variable among affected individuals, this form does shorten life expectancy. (AR), (AD) CLN6 DNAJC5 Type 5 Finnish late infantile (Finnish late infantile variant, vLINCL) – identified in Finland CLN5 Type 6 Variant late infantile (late infantile variant, vLINCL) – identified in Costa Rica, South America, Portugal, the United Kingdom and other nations CLN6 Type 7 CLN7 MFSD8 Type 8 CLN8 Northern epilepsy, progressive epilepsy with mental retardation (EPMR) CLN8 Type 8 Turkish late infantile (Turkish late infantile variant, vLINCL) – identified in Turkey CLN8 Type 9 Identified in Germany and Serbia Unknown, but possibly regulator of dihydroceramide synthase Type 10 CLN10 (congenital, cathepsin D deficiency) CTSD Mutations Infantile form Mannose-6-phosphate Nonsense and frameshift mutations in the CLN1 gene (located at 1p32) always induce classical INCL, while some missense mutations have been associated with ANCL in addition to the infantile and juvenile forms. The mutation typically results in a deficient form of a lysosomal enzyme called palmitoyl protein thioesterase 1 (PPT1). The wild-type PPT1 is a 306-amino acid polypeptide that is typically targeted for transport into lysosomes by the mannose 6-phosphate (M6P) receptor-mediated pathway. Here, the protein appears to function in removing palmitate residues by cleaving thioester linkages in s-acylated (or palmitoylated) proteins, encouraging their breakdown. Defective polypeptides, however, are unable to exit the endoplasmic reticulum (ER), most likely due to misfolding; further analyses of this pathway could serve to categorize INCL among lysosomal enzyme deficiencies. The human PPT gene shows 91% similarity to bovine PPT and 85% similarity to rat PPT; these data indicate that the PPT gene is highly conserved and likely plays a vital role in cell metabolism. In addition, buildup of defective PPT1 in the ER has been shown to cause the increased release of Ca2+. This homeostasis-altering event leads to increased mitochondrial membrane permeability and subsequent activation of caspase-9, eventually leading to an accumulation of cleft and uncleft poly(ADP-ribose) polymerase and eventual apoptosis. Late infantile form The CLN2 gene encodes a 46kDa protein called lysosomal tripeptidyl peptidase I (TPP1), which cleaves tripeptides from terminal amine groups of partially unfolded proteins. Mutations of this gene typically result in a LINCL phenotype. On April 27, 2017, the U.S. Food and Drug Administration approved cerliponase alfa (Brineura) as the first specific treatment for<unk> . It is enzyme replacement therapy manufactured through recombinant DNA technology. The active ingredient in Brineura, cerliponase alfa, is intended to slow loss of walking ability in symptomatic pediatric patients 3 years of age and older with late infantile<unk>  type 2 (CLN2), also known as TPP1 deficiency. Brineura is administered into the cerebrospinal fluid by infusion via a surgically implanted reservoir and catheter in the head (intraventricular access device). Juvenile form All mutations resulting in the juvenile variant of<unk>  have been shown to occur at the CLN3 gene on 16p12; of the mutations known to cause JNCL, 85% result from a 1.02-kb deletion, with a loss of amino acids 154–438, while the remaining 15% appear to result from either point or frameshift mutations. The wild-type CLN3 gene codes for a protein with no known function, but studies of the yeast CLN3 ortholog, the product of which is called battenin (after its apparent connections to Batten’s disease, or JNCL), have suggested that the protein may play a role in lysosomal pH homeostasis. Furthermore, recent studies have also implied the protein’s role in cathepsin D deficiency; the overexpression of the defective protein appears to have significant effects on cathepsin D processing, with implications suggesting that accumulation of ATP synthase subunit C would result. Only recently have studies of human patients shown deficiency of lysosomal aspartyl proteinase cathepsin D. Adult dominant form Between 1.3 and 10% of cases are of the adult form. The age at onset is variable (6–62 yr). Two main clinical subtypes have been described: progressive myoclonus epilepsy (type A) and dementia with motor disturbances, such as cerebellar, extrapyramidal signs and dyskinesia (type B). Unlike the other<unk> s, retinal degeneration is absent. Pathologically, the ceroid-lipofuscin accumulates mainly in neurons and contains subunit C of the mitochondrial ATP synthase. Two independent families have been shown to have mutations in the DNAJC5 gene – one with a transversion and the other with a deletion mutation. The mutations occur in a cysteine-string domain, which is required for membrane targeting/binding, palmitoylation, and oligomerization of the encoded protein cysteine-string protein alpha (CSPα). The mutations dramatically decrease the affinity of CSPα for the membrane. A second report has also located this disease to this gene.
Neuronal ceroid lipofuscinosis
Tay–Sachs disease
Pantothenate kinase-associated neurodegeneration
Infantile neuronal ceroid lipofuscinosis
Glycogen storage disease
Granulovacuolar degeneration
Cerebral creatine deficiency
Familial encephalopathy with neuroserpin inclusion bodies