Levine Critchley Syndrome

To date, confirmation of the identity of the patients with the original NA "Levine-Critchley syndrome" has not been possible. Attempts to trace the New England family described since 1960 by Irving M. Levine (Fig. 1) and others [33, 34, 70, 74-76, 103] have not yet been rewarding. The description of the proband is consistent with ChAc or MLS, particularly the descriptions that "his gait was lurching in character with long strides and somewhat ataxic because of quick involuntary knee buckling movements. ... Speech was moderately inarticulate because it was interrupted by involuntary tongue and facial movements." [75] However, the clinical features of other family members and the pedigree diverge to some extent from the

Fig. 1 Irving M. Levine (right) with Mitchell F. Brin, circa 1985. Photograph courtesy of Dr Mitchell F. Brin

features of patients with molecularly identified ChAc. There was consanguinity five generations previous to the affected family members. Examination of the pedigree shows that chorea was present in one of the proband's siblings, a maternal aunt, and a cousin who had chorea gravidarum [75]. All of these subjects had acan-thocytosis. The neurological findings in many of the other reported family members from four generations are challenging to interpret, and consist predominantly of various combinations of hyporeflexia, mild weakness and muscle atrophy. Acanthocytosis was found mostly in family members with these findings, but did not necessarily cosegregate with the neurological abnormalities. There is apparent male-male transmission excluding the diagnosis of MLS and the inheritance pattern in general appears to be autosomal dominant. However, the variability of the neurological findings, and the presence of acanthocytes in a girl with epilepsy on the father's side of the family, which was otherwise not felt to be affected, make it difficult to draw a conclusion as to the nature of the disorder being described.

The patients reported by Edmund Critchley from two families, one from East Kentucky, USA [22, 23], the other from Lancashire, UK [16, 21], however, display the typical clinical features of genetically confirmed cases [25]. Edmund Critchley (Fig. 2) nicely has summarized his findings [20], most recently in an enjoyable "Neurologist's Tale" [19].

Fig. 2 Edmund Critchley. Photograph courtesy of Dr E.M.R. Critchley

While working at the Department of Neurology of David Barrett Clark in Lexington, Kentucky, it was his task to provide neurologic care in the small towns of the hinterland: "I went about weekly to a regional clinic. We would hire a State limousine, seating at least six people and holding an EEG set, and travel down a state highway at about 90 mph (looking out for helicopters) to a National Park, where we stay the night before an early start treating epilepsy, genetic diseases and other neurological disorders referred to us." [19] In these isolated regions he discovered his "prize patient", for whom he uses the alias Terry. "The poor were white, the Scots-Irish, the inbred white people living along the 'creeks' or narrow river valleys, the Appalachian poor. ... Forced to work on the plantations of Virginia to pay their passage to America, many chose to escape and live rough as frontiersmen. They found a creek with a bit of land, safe from other feuding wild men . married and produced offspring. The progeny moved further along the creek to poorer and poorer land, intermarrying with their own kith and kin" [19].

"Terry had presented to Abe Wikler, Professor of Psychiatry, Neurology and Pharmacy, who had attempted to try to control his movement disorder to no avail. Dave Clark was determined that he should be thoroughly investigated and I was the man to do so Terry was a 29-year-old white male. When first seen at the age of 26, he exhibited involuntary movements and had a grossly swollen, raw, bitten tongue. He had had 15-20 similar episodes of tongue, lip and cheek biting, which often occurred at night. The episodes started 6 years earlier on a background of increased generalized weakness, nervousness, 'fits and jerks', and had increased in frequency and severity. The involuntary movements included finger-snapping, grimacing, dystonic and choreiform movements, hyperextension of the trunk, twisting movements of his shoulders, sucking noises, plosive sounds and drooling. ... There had been times when he could not speak plainly: 'the inside of his mouth would draw', he would 'snap at his lips, and his stomach would stick'. When he ate, his tongue would involuntarily push food out on to his plate. For 4 years he had preferred to retire to a separate room to eat.

"He showed no psychotic or hallucinatory behaviour, but on his later admissions, appeared somewhat disinhibited sexually. Over 2 years, he had two episodes of 'passing out' preceded by abnormal noises and shaking or tremor of the abdomen and outstretched extremities, 'drawing up of the legs'. These episodes, which lasted for 30 min, were followed by confusion and a 'wild look' which persisted for approximately 1 h. On admission in 1967, his involuntary movements were so intense that he could not walk without assistance. He was alert, well-orientated, had no gross memory defects, and was disturbed by his own repulsive appearance. He slurred and stuttered when talking, was often indistinct and had occasional inappropriate laughter. Despite the involuntary movements, there was no ataxia and co-ordination tests were intact. He had generalized hypotonia, flexor plantar responses, and loss of deep tendon reflexes. There was a suspicion of thinning with coarse twitching of his calves. His IQ was 72 (WAIS), verbal 81, and performance 61. ... He was the 10th child.

"The eldest died of seizures, bit her tongue and had involuntary limb movements. She became forgetful, emaciated and bedfast with violent shaking of her limbs. Two others also died about the age of 26. The fourth child had an illness of 2 years duration, with passing out spells and rejection of food from the mouth. The fifth gave birth to an unaffected child and soon afterwards became bedfast and emaciated. The ninth remained healthy till aged 31, before developing choreic movements and grand mal fits. She has always refused admission to hospital but did permit an examination on herself and her normal 17-month child. I witnessed what appeared to be an attack of hystero-epilepsy with partial loss of consciousness, opisthotonus (bending the back in hyperextension) and drawing and grasping movements of all four limbs. Speech and swallowing were normal but she showed facial grimacing sans distal choreic movements. The deep tendon reflexes were absent and the diagnosis of acanthocytosis confirmed" [19].

Critchley provides us with the vivid picture of a severe and progressive neurological condition starting in the third decade in possibly seven male and female siblings (out of ten) from a genetically isolated background favoring inter marriage and manifestation of autosomal recessive traits. He clearly describes severe orofacial dyskinesia with a tongue that would involuntarily push food out on to the plate, generalized chorea severely interfering with gait, sudden trunk flexion and hyperextension, some neuropsychiatry and cognitive impairment and possible epileptic seizures. Critchley also noted the resemblance to the tics of the Gilles de la Tourette syndrome [20].

It is commonly said that "chance favors the prepared mind" and this was certainly true for Edmund Critchley when he happened to see a single patient with an almost identical movement disorder, her parents unrelated, coming from different counties [20]. "Within a year of my return to England, a 30-year old patient was referred to me ... her husband had noticed ... that her walk was ungainly and had avoided drinking with her in company because of her tendency to slobber ... increasingly irritated by grunting noises, of which at first she was unaware. ... She started to lose weight . complaining of intermittent difficulty in swallowing and a tightness in the throat. ... Most disturbing were the wide variety of oro-facial tics ... continually present during waking hours, though fluctuating in severity from day to day . Her speech was dysarthric, partly broken by involuntary movements. She would also grunt, suck, make repetitive sounds, bite her tongue and lower lip, or struggle to control the pooling of saliva. The involuntary limb movements were sometimes dystonic and choreiform with hyperextension and flexion of her trunk and throwing out of an arm or leg ... she took her own life ... A coroner's post-mortem was cursorily performed ..." [19].

All of Critchley's cases appear to have had a phenotype identical to that seen in patients with a molecular diagnosis of ChAc [25]. However, in the absence of genetic testing, we may never know whether Levine-Critchley syndrome truly was ChAc or some other related neurodegenerative disease, making use of the eponym rather imprecise.

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