Hereditary Neuronal Intranuclear Inclusion Disease with Autonomic Failure and Cerebellar Degeneration

OBSERVATION Hereditary Neuronal Intranuclear Inclusion Disease With Autonomic Failure and Cerebellar Degeneration

Raffaella Zannolli, MD; Sid Gilman, MD, FRCP; Simone Rossi, MD; Nila Volpi, MD; Andrea Bernini, MD; Paolo Galluzzi, MD; Daniela Galimberti, MD; Lucia Pucci, PhD; Alfonso D’Ambrosio, MD; Guido Morgese, MD; Fabio Giannini, MD

Background: Neuronal intranuclear inclusion disease conduction and bulbocavernosus reflex studies; auto- (NIID), a multiple-system degeneration, occurs usually nomic function tests; brainstem, visual, somatosensory, and as a sporadic disorder with onset in childhood. The dis- motor evoked potentials; auditory and vestibular testing; ease has been found in monozygotic twins and in sib- metabolic and molecular genetic testing; and muscle and lings. In 2 previously described families, the disorder has rectal biopsy with immunohistochemistry. affected 2 generations. Results: We found variable degrees of ocular dysmet- Objective: To investigate the clinical, anatomical, and ria in 2 cases, ataxic dysarthria and limb ataxia in 1, and electrophysiological characteristics of NIID that affect the hyperreflexia in 2. Magnetic resonance imaging re- central nervous system and the central and peripheral vealed cerebellar atrophy in all 3 cases and diffuse cere- components of the autonomic nervous system in 2 suc- bral cortical atrophy in 1. Results of peripheral nerve con- cessive generations of a family. duction studies were normal. Sphincter EMG findings were abnormal in 2 of the 3 cases, and results of auto- Design: Case report. nomic function tests were abnormal in the same 2. The EMG in 1 case revealed a chronic neurogenic pattern in Setting: Tertiary care hospital. the distal limb muscles. Metabolic and molecular genetic testing revealed no abnormal findings. Results of Patients: A 53-year old woman and her sons, aged 28 the muscle biopsy were negative, but results of the rec- and 25 years. Symptoms began in childhood in 2 of the tal biopsy revealed eosinophilic ubiquitinated intra- 3 cases, and consisted of urinary and fecal inconti- nuclear inclusions in neurons. nence, erectile dysfunction in the men, and recurrent orthostatic hypotension. Conclusion: Transmission of NIID in 2 generations presenting with autonomic failure and cerebellar ataxia was Methods: We used results of clinical neurological evalu- hereditary. ations; cranial magnetic resonance imaging; skeletal muscle and sphincter electromyography (EMG); peripheral nerve Arch Neurol. 2002;59:1319-1326

PROGRESSIVE neurodegen- in multiple systems.20 The inclusions erative disorder, neuronal contain expanded polyglutamine tracts.25-27 intranuclear inclusion The disease frequently appears clinically disease (NIID), usually be- as multiple-system degeneration with the gins clinically in child- dominant features of ataxia, spasticity, hood,A1-17 although adult18-20 and late-life21 parkinsonism, and intellectual impair- onset have been reported. Although NIID ment. It can also present as a visceral neu- appears principally as a sporadic disease, ropathy.22,24 We herein describe a family it has been reported in monozygotic with NIID in 3 members of 2 genera- twins2,6,20 and in siblings.18,22,23 Hereditary tions. Unlike the previously described transmission, possibly autosomal domi- families in whom NIID affected 2 genera- nant, occurs rarely.20,23,24 Distinctive neu- tions, autonomic failure, cerebellar de- ropathological changes characterize the generation, and subtle signs of corticospi- disease and consist of eosinophilic ubiq- nal tract involvement developed in this uitinated intranuclear inclusions in neu- family. The diagnosis was made on the ba- Author affiliations are listed rons of the peripheral, central, and auto- sis of results of a rectal biopsy in 1 of the at the end of the article. nomic nervous system and neuronal loss cases.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 PATIENTS AND METHODS electrocardiographic R-R interval with standard techniques at rest, during deep breathing, during movement from the lying to the standing position, and during the Valsalva All 3 family members underwent evaluation including a his- maneuver.36 We measured blood pressure after 2 minutes tory, medical and neurological examinations, and the spe- in the recumbent position and 3 minutes after standing, cial diagnostic tests listed subsequently. and we recorded the time course of blood pressure variations for 24 hours using standard techniques. AUDITORY AND VESTIBULAR TESTS MUSCLE BIOPSY The tests, previously described,28 included observations of nystagmus, smooth pursuit movements, saccadic move- We performed an open biopsy on the right vastus lateralis ments, optokinetic nystagmus, responses to caloric stimu- muscle of patient 1. lation, and pure tone audiometry. For light microscopic examination, standard histologi- cal and histochemical stains (hematoxylin-eosin, modified IMAGING AND ELECTRODIAGNOSTIC STUDIES Gomori trichrome, myofibrillar adenosine triphosphatase [pH, 9.4], and, after acid preincubation [pH, 4.35 and 4.63], We used cranial magnetic resonance imaging (MRI) at 0.5 periodic acid–Schiff, oil red O, acid phosphatase, nicotin- and 1.5 T and included T1- and T2-weighted images in the amide adenine dinucleotide [reduced form]–tetrazolium re- coronal and sagittal planes. We obtained electromyo- ductase, succinic dehydrogenase, cytochrome-c oxidase, myo- grams (EMGs) of several muscles (ie, brachial biceps, first adenilate deaminase, and phosphofructokinase) were dorsal interosseous muscle of the hand, rectus femoris, tibi- performed on cryostat sections 10 µm thick. Ultrathin sec- alis anterior, and orbicularis oris) to examine the shape and tions from blocks routinely embedded in epoxy resin (Fluka; size of motor unit action potentials and the interference pat- Sigma-Aldrich Corp, St Louis, Mo) were also examined in tern. We examined the external anal sphincter (EAS) and transmission electron microscopy (Philips CM10; Philips, pudendal-nerve terminal motor latency (PNTML) using Eindhoven, the Netherlands). standard techniques.29-31 Using standard surface techniques, we investigated sensory nerve action potentials; con- RECTAL BIOPSY duction velocities of the median, ulnar, and sural nerves; compound muscle action potentials; motor conduction ve- We performed a rectal biopsy under local anesthesia on pa- locities; and distal latencies in the median, ulnar, tibial, and tient 1. A block was longitudinally cut, and a full-length common peroneal nerves.32 We also applied standard ap- specimen was fixed in buffered formalin and embedded in proaches to examine the median, tibial, and pudendal- paraffin. Serial 8-µm-thick sections were stained with he- nerve somatosensory evoked potentials33; the sacral bul- matoxylin-eosin. Immunohistochemistry was performed on bocavernosus reflex32; brainstem auditory evoked potentials; 5-µm-thick sections from the paraffin-embedded block fol- and visual evoked potentials. We evaluated corticospinal lowing preestablished protocols37; sections were incu- tract function with motor evoked potentials to transcra- bated overnight in a 1:1000 dilution of a polyclonal rabbit nial magnetic stimulation.34 antiubiquitin antibody (DAKO, Glostrup, Denmark) and successively in a 1:200 dilution of goat anti–rabbit IgG AUTONOMIC NERVOUS SYSTEM TESTING conjugated to peroxidase (Sigma-Aldrich Corp). Immuno- localization was revealed by means of the chromogen di- We studied the sympathetic skin response (SSR) using stan- aminobenzidine (Sigma-Aldrich Corp). Sections were coun- dard methods in both hands and both feet in all 3 subjects terstained with hematoxylin. For transmission electron and in the penes of the 2 men.35 We obtained 3 or 4 re- microscopy, specimens were fixed in 2.5% glutaralde- cordings of the SSR from each site (palm, sole, and penis) hyde–4% paraformaldehyde in cacodylate buffer and rou- and selected as representative the 2 SSRs with the clearest tinely processed. Immunohistochemistry slides and semi- reproducibility and lowest variability. The latency was ob- thin sections, after toluidine blue staining, were examined tained at the first deflection and the amplitude as the base- with a light microscope (Zeiss Axioplan; Carl Zeiss, Oberko- line to the first peak. The SSR was considered absent if no chen, Germany). Ultrathin sections were contrasted with consistent voltage change occurred at a sensitivity of 50 µV lead citrate and uranyl acetate and observed with an elec- after 3 trials at a slightly painful intensity. We recorded the tron microscope (Philips CM10; Philips).

RESULTS started, the problem was attributed to food intolerance, and in adolescence, to irritable bowel syndrome. At that The Table summarizes the principal clinical features time, investigations revealed no food intolerance, intesti- and the results of the investigations of the 3 patients nal maldigestion or malabsorption, or bacterial or para- examined. sitic pathogens. Additional studies included blood smear; measurement of serum electrolyte, serum urea nitrogen, PATIENT 1 creatinine, calcium, phosphorus, albumin, and total pro- tein levels; a search for specific nutritional deficiency (iron, A 28-year old man was referred to the University of Siena, vitamin B12, folic acid, and vitamin E); testing for antibod- Siena, Italy, with a long-term history of abnormally fre- ies to gliadin and antimysium; and a sweat test.38 His pres- quent intestinal evacuations with more or less fluid stools ent complaints included 2 to 3 daily evacuations of loose and soiling of his underclothing. In childhood, when it stools associated with mild incontinence, resulting in

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Patient No.

123 Clinical Characteristics Sex Male Female Male Present age, y 28 53 25 Patient history First decade of life: chronic soiling; Second decade of life and later: Second decade of life: sporadic fecal second decade of life: mild hypotension with syncope, diffuse and urinary incontinence, faintness incontinence (soiling, fecal and hypohydrosis, mild fecal on moving from lying to standing urinary urgency), weak legs, erectile incontinence (soiling, urgency), position, episodic erectile failure dysfunction; third decade of life: urinary frequency, incomplete gait, speech, and writing bladder emptying; during disturbance, light-headedness on menopause age (45-46 years and moving from lying to standing later): recurrent syncopes, position sudomotor dysregulation General physical and EAS, weak contraction; hyperreflexia; EAS, weak contraction; hyperreflexia; EAS, weak contraction; limb hypotonia neurological cerebellar ataxia; ataxic speech; postural hypotension examination findings dysgraphia; ocular dysmetria Laboratory Tests MRI Atrophy of the cerebellar hemispheres Atrophy of the cerebellar hemispheres Subtle atrophy of the cerebellar and vermis hemispheres; atrophy in the cerebral cortex EEG Normal NE Normal Multimodal evoked potentials SEP (pudendal) Normal NE Delayed SEP (upper/lower Normal Normal Normal limbs) BAEP Normal Normal Normal VEP Normal Normal Normal MEP to TMS Normal Normal Normal EMG EAS Neurogenic Neurogenic Normal PNTML Normal Normal Normal Limbs Normal Neurogenic Normal Sensory and motor NCV Normal Normal Normal Bulbocavernosus reflex Absent NE Delayed SSR (upper/lower Normal Sole of the right foot: delayed; other Normal limbs) limbs: absent 24-Hour BP monitoring Normal Asymptomatic hypotensive episodes, Asymptomatic hypotensive episodes absence of circadian rhythm Postural hypotension None Borderline None Electrocardiographic R-R interval variability Lying to standing Normal Normal Normal Deep breathing Normal Normal Normal Valsalva maneuver Normal Normal Normal Auditory and vestibular Oculomotor overshoot; abnormal Normal Oculomotor overshoot; abnormal testing pursuit movements pursuit movements Karyotype Normal Normal Normal Molecular analysis SCA1, SCA2, SCA3, SCA7, and NE NE Friedreich ataxia genes: negative Muscle biopsy Normal NE NE Rectal biopsy Eosinophilic ubiquinated intranuclear NE NE inclusions in neurons

*Patient 2 is the mother of patients 1 and 3. EAS indicates external anal sphincter; MRI, magnetic resonance imaging; EEG, electroencephalography; NE, not examined; SEP, somatosensory evoked potential; BAEP, brainstem auditory evoked potential; VEP, visual evoked potential; MEP, motor evoked potential; TMS, transcranial magnetic stimulation; PNTML, pudendal-nerve terminal motor latency; NCV, nerve condution velocity; SSR, sympathetic skin response; BP, blood pressure; and SCA, spinocerebellar ataxia.

chronic soiling and occasional fecal incontinence. He also light-headedness when moving from the lying to the stand- complained of urinary urgency. He reported erectile ing position. As a consequence of these symptoms, he dysfunction and lack of morning erections from adoles- stopped participating in sports as a teenager and re- cence to the present. He experienced difficulty with stricted his social activities. The family history was posi- balance, coordination, and strength in his legs since his tive for similar symptoms in his mother and his older second decade of life. He also experienced repeated brother. His father was asymptomatic, and there were no

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12 3 B

Figure 1. Cranial magnetic resonance imaging. A, Midline sagittal T1-weighted image. B, Coronal T2-weighted image. Atrophy of the cerebellar hemispheres is evident in patients 1 (a 28-year-old man) and 2 (the 53-year-old mother of patients 1 and 3) and subtle in patient 3 (the 25-year-old brother of patient 1 and son of patient 2). Vermal atrophy is seen in patient 2. Diffuse cerebral cortical atrophy is seen in patient 3. Images for patients 1 and 2 are 1.5 T; for patient 3, 0.5 T.

other siblings in the family. On general physical exami- evoked potentials tests were also within normal limits. nation, no abnormalities were found except for weak con- Cytogenetic analysis with G-banding at a 550-band reso- traction of the EAS. Results of a neurological examina- lution revealed a normal 46,XY karyotype. Results of mo- tion revealed normal cognitive function. Although full, lecular analyses for the spinocerebellar ataxia (SCA1, extraocular movements showed overshoot dysmetria and SCA2, SCA3, and SCA7) and the Friedreich ataxia genes slow pursuit movements. Speech was slow with an ataxic were negative. Results of a muscle biopsy revealed no myo- dysarthria. The gait was wide based and ataxic, with ir- pathic or neurogenic changes and no histochemical or regular size and directions of individual steps and diffi- ultrastructural evidence of a mitochondrial disease. Re- culty turning without loss of balance. Arm and hand move- sults of rectal biopsy revealed sparse eosinophilic intra- ments were mildly ataxic, and handwriting was consistent nuclear inclusions in neurons, mainly in the myenteric with ataxia. The legs were mildly weak and ataxic in at- plexus. Inclusions were immunoreactive to ubiquitin and tempts at coordinated movement. No parkinsonian fea- consisted of fine filaments (Figure 2). tures were detected. The deep-tendon reflexes were increased, but no clonus was found and the plantar responses PATIENT 2 were flexor. Cranial MRI revealed atrophy of the cerebellar hemi- A woman aged 53 years was the mother of patients 1 spheres (Figure 1, patient 1, A and B). The electroen- and 3. She complained of recurrent syncopal episodes cephalogram revealed normal findings. An H-reflex could with momentary loss of consciousness, usually induced be recorded from the foot muscles at rest, which is an by moving from the lying to the standing position. abnormal finding suggestive of subclinical corticospinal These episodes began when she was about 20 years of tract dysfunction. No evidence was found of a somatic age and had increased in frequency in recent years. She peripheral neuropathy, but the EMG of the EAS re- had been aware of generalized hypohidrosis for most of vealed evidence of denervation consisting of abundant her adult life. She had experienced mild fecal inconti- spontaneous activity at rest and a reduced interference nence consisting of chronic soiling and urgency of def- pattern. The pudendal compound muscle action poten- ecation for many years. She also complained of frequent tial was reduced in amplitude despite a normal PNTML, urination and incomplete voiding during the same and the bulbocavernosus reflex was absent. The R-R in- period. terval variability, SSR, and results of 24-hour blood pres- Results of a general physical examination dis- sure monitoring were normal. Results of multimodal closed no abnormalities except for a weak EAS contrac-

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A C

B D F

Figure 2. Rectal biopsy findings in patient 1. A and B, Ganglia cells from superficial myenteric plexus. Round intranuclear inclusions, surrounded by a thin clear halo, distinctly eosinophilic and demarcated from chromatin (arrows), are seen. A faintly visible nucleolus is seen close to the eosinophilic inclusion (asterisk) (hematoxylin-eosin, orignal magnification ϫ1000). C and D, Ubiquitin staining of inclusions (inset) diffuses to the nucleus (arrows and asterisk) (antiubiquitin immunoperoxidase, original magnification ϫ1000). E, Semithin section. Hyaline appearance of the inclusion (arrow) is seen, close to the nucleolus (asterisk) (toluidine blue, original magnification ϫ1000). F, Nuclear inclusion (arrows) consisting of intermingled fine filaments, most of which transversally sectioned, with no defined spatial array. Bar indicates 1 µm (transmission electron microscopy, original magnification ϫ10500).

tion. Results of a neurological examination revealed nor- 24 hours showed continuous but asymptomatic hypo- mal cognition, speech, and cranial nerve functions. tension, without variations of circadian rhythm (mean Extraocular movements were normal. Results of the mo- daytime systolic and diastolic blood pressure, 102.8 and tor system examination were also entirely normal, with 69.5 mm Hg, respectively; mean nighttime values, 100.8 no ataxia or parkinsonian features. The deep-tendon re- and 67.0 mm Hg, respectively). During the physical ex- flexes were diffusely hyperactive, but without clonus and amination, the blood pressure in the supine position was with flexor plantar responses. Cranial MRI revealed at- 105/70 mm Hg and 85/60 mm Hg 3 minutes after stand- rophy of the cerebellar vermis and hemispheres (Figure ing. Results of the multimodal evoked potentials tests were 1, patient 2, A and B). She refused to undergo electro- within normal limits. Cytogenetic analysis with G- encephalography. The EMG showed a chronic neuro- banding at the 550-band resolution revealed a normal genic pattern in the distal muscles of the upper and lower 46,XX karyotype. limbs. Although results of motor and sensory nerve conduction studies were normal, the findings suggested a mild PATIENT 3 subclinical motor axonal peripheral neuropathy. The EMG of the EAS revealed abnormal spontaneous activity at rest A 25-year old man had a history of intermittent fecal and (fibrillations and positive wave potentials) and a re- urinary incontinence and episodic erectile failure that be- duced interference pattern, indicating denervation. More- gan sometime in adolescence. He also reported mild light- over, the pudendal compound muscle action potential headedness on moving from the lying to the standing po- was reduced in amplitude, despite a normal PNTML. The sition. He had noted joint laxity for many years. SSR was abnormal, with reduced amplitude and delayed Results of a general physical examination revealed response from the sole of the right foot and absent re- marked hypotonia and joint laxity of the limbs. Results sponses from other limbs. Results of the R-R interval vari- of a digital rectal examination showed weak contraction ability study were normal. Blood pressure monitoring for of the EAS. On neurological examination, cognitive func-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 tion was intact. Results of oculomotor testing showed extremity in patient 1 probably resulted from corticospi- overshoot dysmetria and slow pursuit movements. No nal disease. abnormalities were detected in speech or in other cra- Laboratory investigations confirmed the clinical im- nial nerve functions. Examination of the motor system pressions and added new information. The EMG of the revealed no abnormalities, and the deep-tendon re- EAS revealed a neurogenic pattern in 2 of the 3 cases, in- flexes were normal, with flexor plantar responses. dicating denervation. Moreover, in both of these cases, the Cranial MRI showed subtle cerebellar hemisphere at- pudendal compound muscle action potential was re- rophy and diffuse cerebral cortical atrophy (Figure 1, pa- duced in amplitude, despite a normal PNTML. These find- tient 3, A and B). The electroencephalogram was normal. ings indicate degeneration of the Onuf nucleus, which is The EMG of the limb musculature showed no abnormal- located in the anterior horn of sacral segments 2, 3, and 4 ity, and no clinical or electrophysiological evidence of a and supplies the striated sphincter muscles by way of the peripheral neuropathy was found. Despite the weak EAS pudendal nerves. In one son, the bulbocavernosus reflex contraction on digital examination, EMG of the EAS, am- was absent, and in the second it was delayed, providing plitude of the pudendal motor response, and PNTML were further evidence of autonomic failure and demonstrating normal. The bulbocavernosus reflex, however, showed a the neurogenic basis of the erectile dysfunction. markedly delayed response (58.2 milliseconds; normal, In patient 2, who had a history of hypohidrosis, the Ͻ42.5 milliseconds).39 The cortical component of the pu- SSR was abnormal in the limbs. The SSR serves as an in- dendal somatosensory evoked potential was also mark- dex of peripheral autonomic nerve activity, especially for edly delayed (45.6 milliseconds; normal, Ͻ41.2 millisec- sudomotor function of postganglionic unmyelinated onds).40 Results of autonomic function tests all were within sympathetic fibers.41 In this same patient, the EMG re- normal limits, but the 24-hour blood pressure monitor- vealed a chronic neurogenic pattern in the distal limb ing showed some asymptomatic episodes in which the muscles, suggesting a subclinical motor axonal periph- blood pressure declined to 78/55 mm Hg. The multimo- eral neuropathy. In 2 family members, hyperreflexia dal evoked potentials were normal. Cytogenetic analysis suggested corticospinal tract involvement, and in 1 of these with G-banding at 550-band resolution revealed a nor- (patient 1), an H-reflex could be recorded from the foot mal 46,XY karyotype. muscles at rest, providing further evidence of corticospinal involvement. Since motor evoked potentials to COMMENT transcranial magnetic stimulation, which reflect the func- tionality of the fastest corticospinal fibers,34 were nor- We present, to our knowledge, the first report of 2 suc- mal, the hyperreflexia probably resulted from dysfunc- cessive generations of a family with NIID that affected tion of small myelinated fibers of the corticospinal tracts.42 the central nervous system and the central and periph- All 3 family members complained of orthostatic light- eral components of the autonomic nervous system. This headedness, but measurements of orthostatic changes in report is also the second of central nervous system NIID blood pressure revealed orthostatic hypotension only in that affected 2 successive generations of a family. In the patient 2. Moreover, 24-hour blood pressure monitor- first report,20 neurogenic weakness developed in female ing demonstrated only asymptomatic hypotensive epi- monozygotic twins in adult life, followed by cerebellar sodes in 2 family members. ataxia, dysarthria, and death after 20 years. An identical Although no history of a similar disorder in previ- illness developed in 2 adult sons of 1 twin. In another ous generations could be ascertained, the 3 affected mem- family, NIID affected 2 generations with a visceral neu- bers of this family provide further evidence of an inher- ropathy manifested as chronic idiopathic intestinal ited form of NIID, possibly by means of autosomal pseudo-obstruction, and results of rectal biopsy estab- dominant inheritance. In the previously described fam- lished the diagnosis.23,24 The remaining reports of NIID ily with NIID of the central nervous system20 and the pre- concern sporadic cases except for occasional cases in- viously described family with visceral NIID,23,24 only 2 volving monozygotic twins2,6 or siblings.18,22 generations were affected, and the transmission was con- We describe herein 3 members of a family affected sidered to be autosomal dominant. The absence of simi- by a neurological disorder involving multiple systems that lar disorders in previous generations in all 3 families sug- began in the first or second decade of life and progressed gests the possibility of a spontaneous mutation in the gene slowly. Autonomic disorders appeared first, consisting of responsible for NIID. Such a mutation could also ac- fecal and urinary incontinence of varying degrees, accom- count for the previous reports of NIID affecting mono- panied by postural hypotension and hypohidrosis in 1 case zygotic twins2,6 and siblings.18,22 and erectile dysfunction in both male members. In 1 fam- Achieving a correct diagnosis of the disorder in this ily member, cerebellar dysfunction affected speech, ocu- family proved challenging and triggered an extensive di- lomotor function, and limb coordination, and structural agnostic evaluation. The rectal biopsy was the only method imaging revealed widespread cerebellar atrophy. The other that allowed the correct diagnosis to be made in a living 2 members also had widespread cerebellar atrophy, patient. The constellation of symptoms in these cases but with only minor clinical manifestations in 1 of the bore some similarity to a previously described multiple- 2, consisting principally of mildly abnormal extraocular system degeneration resulting from the SCA1 gene.43 In movements. Hyperreflexia with normal plantar re- the patients in this previous report, a cerebellar ataxia sponses in 2 of the members suggested mild corticospi- accompanied by autonomic insufficiency, dystonia, and nal involvement in addition to the autonomic and cer- peripheral neuropathy developed. The onset was much ebellar involvement, and mild weakness of the lower later in life than in the current cases, however, and the

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 autonomic failure was not as severe. Moreover, results drafting of the manuscript (Drs Zannolli, Rossi, Volpi, Ber- of genetic testing for the SCA1 gene (and also for the nini, Galluzzi, Galimberti, Pucci, D’Ambrosio, Morgese, and SCA2, SCA3, and SCA7 genes) were negative in the pre- Giannini); critical revision of the manuscript for important sent family. This family’s disease also bears some clini- intellectual content (Drs Zannolli, Gilman, Rossi, Volpi, Ber- cal resemblance to familial amyloidotic polyneuropathy nini, Galluzzi, Galimberti, Pucci, D’Ambrosio, Morgese, and associated with cerebellar ataxia and signs of cortico- Giannini); obtained funding (Drs Zannolli and Morgese); spinal tract dysfunction.44,45 This diagnosis was ruled administrative, technical, and material support (Drs Zan- out in the present cases by results of the peripheral nolli, Rossi, Volpi, Bernini, Galluzzi, Galimberti, Pucci, nerve studies, which provided no evidence of an overt D’Ambrosio, Morgese, and Giannini); and study supervi- somatic polyneuropathy. Familial dysautonomia, the sion (Drs Zannolli, Gilman, Morgese, and Giannini). Riley-Day syndrome, results from a genetic disorder Corresponding author and reprints: Raffaella Zannolli, mapped to chromosome 9q31-q33.46,47 This autosomal MD, Department of Pediatrics, Obstetrics, and Reproductive recessive disorder affects the Ashkenazi Jewish popula- Medicine, Section of Pediatrics, Policlinico Le Scotte, Univer- tion, causing developmental loss of neurons from the sity of Siena, Siena, Italy (telephone: 390577586514; fax: sensory and autonomic nervous system. The mode of 390577586143; e-mail: [email protected]). inheritance, ethnic background, and absence of sensory abnormalities made this diagnosis unlikely in the pre- REFERENCES sent family. A mitochrondrial DNA mutation presented

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