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Conjugal amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive degeneration of motor neurons in the motor cortex, brainstem, and spinal cord (1-3). This motor neuron disease occurs sporadically in 90% of cases, with the etiology remaining largely unknown. It is familial in only 5% to 10% of cases, with 20% of those being linked to a mutation in the SOD1 gene and another 2% to 5% of cases being linked to a mutation in the TDP-43 gene (1, 2). Recently, mutations in the FUS/TLS gene and the C9ORF72 gene have also been implicated in familial ALS (4, 5). The average age of onset for familial ALS is 50 years, while sporadic cases have an average age of onset of 60 years (3). Conjugal ALS is rare and is commonly felt to occur as a chance association. We report a case of conjugal ALS in our outpatient neurology clinic.

CASE PRESENTATION

A 45-year-old right-handed white woman was seen in neurological consultation at the Muscular Dystrophy Association Clinic. The patient had seen multiple physicians, including neurologists, regarding her symptoms and received a thorough workup at two major centers, the results of which were reviewed. Her workup included numerous laboratory studies and electro-diagnostic studies, which were not repeated. Her findings were felt to be consistent with motor neuron disease.

The patient initially presented with pain in her neck and shoulders, waxing and waning in character, associated with symptoms of a flaccid bladder. Initially, the pain was attributed to the patient's occupation, as she had worked as a hairdresser, and she was treated symptomatically without relief. The patient's laboratory workup was negative except for dyslipidemia, a low folate level, hypothyroidism, and an elevated creatine kinase level of 472 U/L.

The patient had symptoms of dysarthria, dysphagia, difficulty identifying when her bladder was full, and incontinence. The timeline of her symptoms after initial presentation through her death 6 years later is shown in the Table.

Twelve years after her death, the patient's 66-year-old non-consanguineous husband presented to the same neurology office with dysarthria and diffuse fasciculations in the tongue and all four limbs. The only finding on his neurologic exam was intrinsic hand muscle weakness and +3/4 brisk upper limb reflexes. His symptoms had begun approximately 6 weeks prior to presentation after waking up one morning with a voice change almost overnight. Two to three weeks later, he had started to slur his words and had occasional difficulty swallowing. He then developed muscle twitching in his right arm.

The patient stated that prior to the onset of these symptoms, he had undergone a fundoplication after which he was told he had been hypoxic for an unknown amount of time with an oxygen saturation in the 60s. He stated that since then, he was unable to think well, was unable to do things he used to be able to do, and required in-home assistance.

The patient had a history of hypertension and hyperthyroidism. He had previously had iatrogenic thyrotoxicosis, which had resolved. The patient's endocrine panel, autoimmune panel, heavy metal screen, tick panel, and serum protein electrophoresis results were normal. Initial electromyography (EMG) of the bilateral lower limbs and left upper limb revealed insertional abnormalities in the form of positive sharp waves, resting fasciculation potentials, and some fibrillation potentials. Voluntary potentials were normal. Motor nerve conduction velocities in the left median, left ulnar, and bilateral tibial and peroneal nerves were normal, as were terminal motor latencies. Distal sensory latencies were absent in the left ulnar, median nerves, and bilateral sural nerves related possibly to an asymptomatic incidental polyneuropathy. Magnetic resonance imaging of the brain was consistent with ischemic white matter changes from small-vessel disease with no evidence of enhancing lesion or acute abnormalities. The patient was diagnosed with bulbar-onset conjugal ALS and referred to another center for a second opinion. An SOD1 mutation analysis was performed for the patient's daughter, and the result was negative.

One month after initial presentation, the patient presented to the Integris MDA Neuromuscular Center for a second opinion in which the diagnosis of ALS, bulbar onset was confirmed. Three months after initial presentation, the patient developed increasing weakness, multiple falls requiring the use of a walker, dysphasia, and worsening dysarthria. His physical exam revealed bifacial and posterior neck weakness as well as increased atrophy and decreased speed of lateral movement of the tongue with unintelligible speech. Pulmonary function was assessed with a forced vital capacity of 18% seated and 16% supine and a negative inspiratory force of 8.

Repeat EMG done at the Integris MDA Neuromuscular Center revealed normal left median motor nerve conduction velocity with prolonged distal latency and reduced amplitude. Left ulnar motor conduction showed prolonged distal latency and reduced amplitudes but no focal conduction block. Left median sensory study showed prolonged peak latency with very small amplitude and no recording from the index finger. EMG of the left arm, leg, and rectus abdominus muscles showed diffuse acute and chronic denervation with fasciculations. Widespread motor neuron disease was suggested. These findings associated with denervation in the tongue met El Escorial criteria for ALS.

Baclofen was initiated for the patient's symptoms of muscle cramping, a neuropsychiatry consult was performed, and speech and swallow evaluation and communication device referral was completed. The use of noninvasive ventilator assistive devices was initiated as the patient developed a rapid progression of diaphragmatic weakness. The patient wished to go on a trip to China, which he completed; however, he died shortly thereafter.

No common exposures were identified between the two patients in regards to environmental toxins, pesticides, metal toxins, or occupational toxins. In addition, they were not farmers and were not exposed to ground water. There was also no history of trauma, alcoholism, or military service.

DISCUSSION

The most commonly used diagnostic criteria for ALS are the 1994 El Escorial criteria and the revised 2000 Airlie House criteria (1, 2). These criteria are used mainly for research studies, however, as the diagnosis remains mostly clinical. The El Escorial criteria classify the ALS through signs and symptoms as definite, probable, probable with laboratory support, possible, or suspected (1).

Patients presenting with the spinal-onset form of ALS will experience an insidious progressive painless weakness beginning with upper or lower extremities, atrophy of muscles, and fasciculations (1-3). Patients will usually develop hyperreflexia and an extensor toe sign. On the other hand, 20% to 33% will have a bulbar-onset form of ALS characterized by dysarthria, dysphagia, tongue atrophy, and tongue fasciculations (1-3). Pseudobulbar symptoms such as emotional lability are also common (1-3). Sensation and bowel and bladder function remain intact. Fifty percent of patients do not survive past 3 years, and most succumb to respiratory failure (3).

The incidence of sporadic ALS ranges from 1.5 to 2.7 per 100,000, and the prevalence is 5.2 to 6.0 per 100,000 (1, 2). The lifetime probability of conjugal ALS is more rare, calculated at 1 in 510,000 couples (6). Surprisingly, through 1975, up to 10 conjugal pairs of ALS were recognized in Guam alone (7), where ALS is 50 to 100 times more prevalent (2, 7, 8). The prevalence there is now declining.

Outside of Guam, however, conjugal ALS remains rare. In consideration of the incidence and population in the United States, we would expect to see approximately 4 cases of conjugal ALS per year (3). The incidence, however, is much less. Through 2009, there were reports of 19 conjugal ALS pairs in the literature. This case is the 20th pair. There was a cluster of 9 pairs from France (9, 10), 4 pairs from Italy (7, 11-13), 2 pairs from Brazil (14), 1 pair each from India (15) and Spain (16), and 2 other pairs from the United States (6, 8). As it stands presently, a single unifying or common exposure between pairs cannot be found. No pairs were consanguineous, and all pairs had lived together for at least 10 years prior to diagnosis (10, 11, 13).

(1.) Mitchell JD, Borasio GD. Amyotrophic lateral sclerosis. Lancet 2007;369(9578):2031-2041.

(2.) Wijesekera LC, Leigh PN. Amyotrophic lateral sclerosis. Orphanet J Rare Dis 2009;4:3.

(3.) Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, Burrell JR, Zoing MC. Amyotrophic lateral sclerosis. Lancet 2011;377(9769):942-955.

(4.) Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, Horvitz HR, Landers JE, Brown RH Jr. Mutations in the FUS/ TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 2009;323(5918):1205-1208.

(5.) Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, Schymick JC, Laaksovirta H, van Swieten JC, Myllykangas L, Kalimo H, Paetau A, Abramzon Y, Remes AM, Kaganovich A, Scholz SW, Duckworth J, Ding J, Harmer DW, Hernandez DG, Johnson JO, Mok K, Ryten M, Trabzuni D, Guerreiro RJ, Orrell RW, Neal J, Murray A, Pearson J, Jansen IE, Sondervan D, Seelaar H, Blake D, Young K, Halliwell N, Callister JB, Toulson G, Richardson A, Gerhard A, Snowden J, Mann D, Neary D, Nalls MA, Peuralinna T, Jansson L, Isoviita VM, Kaivorinne AL, Holtta-Vuori M, Ikonen E, Sulkava R, Benatar M, Wuu J, Chio A, Restagno G, Borghero G, Sabatelli M; The ITALSGEN Consortium. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011;72(2):257-268.

(6.) Cornblath DR, Kurland LT, Boylan KB, Morrison L, Radhakrishnan K, Montgomery M. Conjugal amyotrophic lateral sclerosis: report of a young married couple. Neurology 1993;43(11):2378-2380.

(7.) Poloni M, Micheli A, Facchetti D, Mai R, Ceriani F, Cattalini C. Conjugal amyotrophic lateral sclerosis: toxic clustering or change? Ital J Neurol Sci 1997;18(2):109-112.

(8.) Chad D, Mitsumoto H, Adelman LS, Bradley WG, Munsat TL, Zieper I. Conjugal motor neuron disease. Neurology 1982;32(3):306-307.

(9.) Camu W, Cadilhac J, Billiard M. Conjugal amyotrophic lateral sclerosis: a report on two couples from southern France. Neurology 1994;44(3 Pt 1):547-548.

(10.) Corcia P, Jafari-Schluep HF, Lardillier D, Mazyad H, Giraud P, Clavelou P, Pouget J, Camu W. A clustering of conjugal amyotrophic lateral sclerosis in southeastern France. Arch Neurol2003;60(4):553-557.

(11.) Rachele MG, Mascia V, Tacconi P, Dessi N, Marrosu F, Giagheddu M. Conjugal amyotrophic lateral sclerosis: a report on a couple from Sardinia, Italy. ItalJNeurol Sci 1998;19(2):97-100.

(12.) Paolino E, Granieri E, Tola MR, Rosati G. Conjugal amyotrophic lateral sclerosis. Ann Neurol 1983;14(6):699.

(13.) Chio A, Herrero Hernandez E, Discalzi G, Ghiglione P, Di Vito N, Calvo A, Vercellino M, Plano F, Mutani R. Conjugal amyotrophic lateral sclerosis: suggestion for the implication of environmental factors. Amyotroph Lateral Scler Other Motor Neuron Disord 2001;2(3):165-166.

(14.) Godeiro Jr C, Oliveira AS, Felicio AC, Chieia MA, Gabbai AA. Conjugal amyotrophic lateral sclerosis in Brazil. Arq Neuropsiquiatr 2009;67(4):1045-1048.

(15.) Maloo JC, Radhakrishnan K, Poddar SK, Thacker AK. Conjugal motor neurone disease. J Assoc Physicians India 1987;35(4):303-304.

(16.) Martinez Matos JA, Martinez Ferri M, Arbizu Urdiain T, Montero J. Esclerosis lateral amiotrofica conyugal. Neurologia 1986;1(3):135-136.

John D. Dewitt, DO, Julia Kwon, DO, Rebecca Burton, DO, and Jeffrey S. Stroup, PharmD

From the Department of Internal Medicine, Oklahoma State University Medical Center, Tulsa, Oklahoma (Kwon, Burton, Stroup). Dr. Dewitt is a neurologist in private practice in Tulsa, Oklahoma.

Corresponding author: Jeffrey S. Stroup, PharmD, BCPS, Associate Professor of Medicine, Oklahoma State University Center for Health Sciences, 635 West 11th Street, Tulsa, Oklahoma 74127 (e-mail: Jeffrey.Stroup@okstate.edu).
Table. Progression of symptoms for patient 1

Months
after initial
presentation    Symptoms

3               Difficulties with gait and balance, an immobile palate,
                spastic dysarthria, tongue fasciculations, increased
                tone in both upper and lower extremities, sustained
                clonus, and bilateral upgoing toes

6               Wasting of the upper and lower extremities with
                dependent edema

9               Continued deterioration of speech, hypertonic upper and
                lower extremities

13              Inability to walk

17              Near anarthria, confined to a wheelchair

21              Inability to support her head, complete quadriplegia

28              Many pain complaints and feelings of "smoldering
                sensations" at night

57              Recurrent urinary tract infections from bladder
                dysfunction and pulmonary infections from aspiration,
                increased pain

70              Anarthria with an atrophic tongue furrowed with
                fasciculations, immobility with a spastic
                quadriparesis, need for total custodial care

76              Death
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Author:Dewitt, John D.; Kwon, Julia; Burton, Rebecca; Stroup, Jeffrey S.
Publication:Baylor University Medical Center Proceedings
Article Type:Clinical report
Geographic Code:1USA
Date:Jan 1, 2012
Words:2081
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