Recurrent mutations in DNAJC5 cause autosomal dominant Kufs disease.

We sought to identify the molecular basis of the autosomal dominant form of Kufs disease, an adult onset form of neuronal ceroid lipofuscinosis. We used a combination of classic linkage analysis and Next Generation Sequencing to map and identify mutations in DNAJC5 in a total of three families. We analyzed the clinical manifestations in 20 individuals with mutation in DNAJC5. We report here the mapping and the identification of a p.L116del mutation in DNAJC5 segregating with the disease in two distinct American families, as well as a p.L115R mutation in an additional family. The age of onset and clinical manifestations were very homogeneous among mutation positive individuals, including generalized tonic-clonic seizures, myoclonus, ataxia, speech deterioration, dementia, and premature death. A few individuals also exhibited parkinsonism. DNAJC5, which encodes the cysteine string protein (CSPα), a presynaptic protein implicated in neurodegeneration, causes autosomal dominant Kufs disease. The leucine residues at positions 115 and 116 are hotspots for mutations and result in a homogeneous phenotype of progressive myoclonus epilepsy with onset around 30 years old.

Graphic representation of carotid artery bruits.

Auscultation of the neck for detection of bruits over the carotid arteries has become a necessary part of any complete physical examination. Early detection of atherosclerotic occlusive disease in these vessels can play a major role in prevention of stroke. Such findings have previously been recorded as word descriptions in varying degrees of detail. A method is presented for quickly and easily recording the presence and character of cervical bruits, plus additional important information, including blood pressure, pulse, heart rhythm, prior vascular surgery, and known occlusion in these vessels. The figure used allows others to rapidly perceive this information and enables ready comparison on successive examinations.

Prevention of recurrent stroke.

Victims of atherothrombotic infarction of the brain, the most common variety of stroke, frequently have recurrent strokes. Risk factors believed to accelerate such events include hypertension, diabetes mellitus, hyperlipidemia, atherosclerotic disease (of heart, aortocervical and intracranial vessels), erythrocythemia, stress, tobacco smoking, hyperuricemia, and perhaps obesity. Most prior studies indicate average anticipated 5 year mortality of 35 to 65 percent and stroke recurrence rate of 20 to 40 percent. A consistent effort to control risk factors in 88 survivors of a first cerebral infarction yielded 17 percent mortality and 16 percent stroke recurrence rates during the 5 years following first stroke. This sustained and systematic approach to risk factor management seemed beneficial to these stroke victims.

On the neurochemistry of an adult form of ceroid lipofuscinosis (Kuf's disease).

Little progress has been made in procedures for diagnosis of this baffling group of diseases known as ceroid lipofuscinoses (CL), which exhibit infantile, juvenile, and adult forms. Although these have been shown for the most part to be genetic in origin, the enzymatic or other defects leading to accumulation of lipopigments in tertiary lysosomes of neurons or astrocytes re unknown. Among the more commonly discussed theories is the role of peroxy radicals or their products formed by lipoperoxidation of polyunsaturated fatty acids. Although peroxy radicals are damaging to tissues and biological processes, no differences were observed in levels of leucocyte peroxidase (metabolizing H2O2) for Kuf's patients in comparison to age-matched controls. Also, no differences were observed in levels of blood factors that affect the rates of lipoperoxidatin by rat or human brain homogenates in vitro (measured by formation of MDA or other TBA positive materials).

Preventing stroke after TIA.

Previous reports suggest the probability of stroke after TIA as 20 percent in the first year and 45 percent within five years. Forty-five TIA victims were treated in a stroke prevention program for an average of five years. Efforts were made to correct or control all risk factors. Eight of the 45 experienced further TIA'S, Three had subsequent strokes and two had myocardial infarctions. Two deaths were reported. This stroke prevention program offers an improved prognosis for victims of TIA.

Conjunctival microangiopathy. An early sign of degenerative vascular disease?

Biomicroscopic examination of the bulbar conjunctival vessels regularly discloses degenerative microangiopathy in patients with overt arteriosclerotic cerebral vascular disease. Examination of a group of normotensive nondiabetic adults aged 21 to 39 years disclosed similar but less severe changes in 56 per cent of the men and 26 per cent of the women. The incidence was higher (88 per cent of the men and 45 per cent of the women) in those with a strong family history of early death from arteriosclerotic disease. There was no consistent correlation between the severity of the microangiopathy and the values for hematocrit, cholesterol, triglycerides or blood pressure. Conjunctival microangiopathy, like atherosclerosis of larger vessels, starts in the second and third decades and advances with age. We suggest that microangiopathic changes in the conjunctival vessels may provide the first readily detectable evidence of degenerative vascular disease.

Nervous system affections caused by the mumps virus.

Hippocrates probably first described mumps parotitis, but not until 1758 was affection of the central nervous system reported in this disease. Mumps meningitis, encephalitis, myelitis, polyradiculitis and cranial neuritis are now well known, and may occur without clinical parotitis. Meningitis occurs most commonly, encephalitis, cranial neuritis and polyradiculitis less often, and myelitis rarely. They may present individually or in combination. A patient is described who first developed acute mumps meningoencephalitis, without clinical parotitis. Transverse myelitis occurred two weeks later, and finally optic neuritis ten days following the myelitis. Slow but complete recovery followed. Attention is directed to the various ways mumps can affect the nervous system. This virus should always be considered among possible etiologic agents causing such neurologic syndromes.

Leukocyte peroxidase deficiency in a family with a dominant form of Kuf's disease.

Use of a spectrophotomtetric assay of peroxidase with p-phenylenediamine as cosubstrate demonstrated deficient enzymne activity in leukocytes from two patients with a dominantly inherited form of ceroid lipofuscinosis (Kuf's disease) and a clinically hlealthy unaffected sibling. When the reaction was performned in the absence of added hydrogen peroxide, oxidation of the p-phenylenediamnine cosubstrate (indicating the presence of endogenous peroxide) occurred only with enzyme samnples from the three siblings but not with those from a large number of unrelated, unaffected controls. This demonstrates that the deficiency of peroxide) found previously in the recessively inherited infantile and juvenile formns of ceroid lipofuscinosis (Batten-Spielmeyer-Vogt disease) is also present in an adult form with dominant inheritance.