- Email: [email protected]
Wolfram syndrome
International Journal of Pediatric Otorhinolaryngology (2004) 68, 243—247
CASE REPORT
Wolfram syndrome David Megighian, Marina Savastano* Dipartimento di Specialità Medico-Chirurgiche, Sezione ORL, Padua University, Via Giustiniani 2, 35128 Padua, Italy Received 1 June 2003 ; received in revised form 30 September 2003; accepted 8 October 2003
KEYWORDS Wolfram syndrome; Main and associated anomalies; Diagnosis
Summary The Wolfram syndrome is a rare dysmorphogenetic disease of autosomic recessive hereditary nature. The pathogenesis of the disease is still not well known. It is characterised by the presence of diabetes insipidus, diabetes mellitus, optic atrophy and deafness. Other anomalies, such as renal outflow tracts and multiple neurological disorders may develop later. In our case report the diabetes mellitus appeared at the age of 4; the hearing loss and renal disturbances at the age of 11; the optic atrophy at the age of 16. No signs of ataxia, diabetes insipidus and neurologic anomalies were found. The diagnosis of Wolfram syndrome is not always easy in the first stages of the disease. The suspect may come from the presence of a juvenile diabetes mellitus asssociated with optic atrophy. For the diagnosis a valid clue can be given from the results of some clinical tests such as the positivity of the visual evoked potentials and the retinogram reliefs and the exclusion of the autoimmune origin of the diabetes mellitus. Other signs such as the progressive sensorineural hearing loss, the presence of nystagmus and of urodynamic disturbances and renal complications makes the diagnosis of this syndrome easier. © 2003 Elsevier Ireland Ltd. All rights reserved.
1. Introduction In 1938 Wolfram for the first time observed, and then with Wagener described, a clinical feature characterised by diabetes mellitus, optic atrophy and deafness [1]. These anomalies appeared in four brothers in different periods during the first and second decades of life. An atypical form of ataxia occurred in one of these patients and there was a neurological vesica in another later. In the following years, other anomalies, diabetes insipidus, neuropsychical and endocrinal disturbances, were added, thus increasing the original symptomatological feature. For this reason the same Wolfram syn∗ Corresponding author. E-mail address: [email protected] (M. Savastano).
drome is defined with the term Wolfram DIDMOAD syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, deafness) in literature [2—7]. It is a recessive hereditary disease; its pathogenesis is still little known [8—10].
2. Case report D.N.C., 13-year-old, hospitalised by the Urological department because affected by hydronephrosis, due to a suspected neurological vesica and the outcome of bilateral nephrostomia. He is the son of consanguineous (first cousins) parents, who are healthy as is the older sister. On the basis of the anamnesis there is no hereditary disease in the ascendants. From the age of 4, because of the onset of diabetes mellitus, the patient undergoes insulinic
0165-5876/$ — see front matter © 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijporl.2003.10.012
244
dB 0 10 20 30 40 50 60 70 80 90 100 110 120
250 500 1000 2000 4000 8000 10000
Fig. 1 years.
Nº of jerky eye movements
therapy. The glycemia has been well compensated till now. There is no diabetes insipidus present, a complication which in some cases may occur also later, caused by a degenerative alteration of the nervous cerebral structures at the level of the supraoptic and paraventricular districts. During hospitalisation the patient underwent various tests. A urovideodynamic test reveals, besides bilateral hydronephrosis, a pluridiverticolar vesica with hyperreflexic waves of twitch. A renal angiophotoscintigraphy with closed nephrostomy, indicates a functionality of 81% in the left kidney and of 19%. in the right kidney. There are no signs of neurologic disturbances but from the neuropsychiatric point of view there is a risk of depression because of obsessive attention to his physical problems. An internal check-up reveals too much weight because of reduced physical activity. The oculistic examination does not reveal any sign of diabetic retinopathy. The papillae are pale-rosy and the peripheric vessels and the maculae are regular. The pupillar reflexes are very slow. The visual deficit is progressively worsening. At the age of 14 the visus is still 2/10 bilaterally but an exotropya appears on the left eye. After 1 year his visus is reduced to 1/10 only in the right eye. At the age of 16 in the right eye it is only possible to count fingers from 2 m; in the left eye the visus is reduced to 1/10. The first sign of optic atrophy appears. After another year the finger count was reduced to 1 m in the right eye, while the visus remains 1/10 in the left eye. The signs of optic atrophy are more evident. At the age of 18 the finger count is reduced to 50 cm, the visus remains 1/10 in the left one. The electroretinogram is normal and there is absence of retina—cortical conduction at the evoked visual potentials. The visus is today unchanged. The ENT examination is normal while the liminar audiometry demonstrates a bilateral symmetric sensorineural hearing loss prevalent for the medium-high frequencies. Considering the entity of the hearing handicap, two hearing aids were applied (Fig. 1). The auditory brain stem responses (ABR) indicate a little increase in the V wave latency at 80 dB of stimulus intensity. From a vestibular point of view, two types of nystagmus are present: one is a horizontal jerky nystagmus towards the left with a rotary component and the other one is an upbeat vertical nystagmus. As far as the opticcynetic stimulation is concerned, the opticcynetic horizontal nystagmus (NOC) is bilaterally altered while the evoked vertical NOC appears normal. The caloric stimulation by Veits (20◦ ) is normal (Fig. 2).
D. Megighian, M. Savastano
Hz
Liminar audiometry feature at the age of 13
100 90 80 70 60 50 40 30 20 10
right ear left ear stimulation stimulation
horizontal nystagmus
upbeat vertical nystagmus
Fig. 2 Numbers of jerky eye movements, at the caloric stimulation by Veits (20◦ ) and numbers of jerky eye movements of horizontal and vertical nystagmus.
The psychological condition has worsened because the patient is not able to accept the deficit of the visual and auditory functions.
3. Considerations The Wolfram syndrome is a rare dysmorphogenetic disease, which affects 1 every 500,000 young people. According to Barrett et al. [11] this incidence seems to be greater in consanguineous parents (as in the case described by us), but the possibility that the same clinical form may appear also in relatives of eterozygotous subjects cannot be excluded. The autosomic recessive hereditary nature of the disease has been confirmed by studies made on a large number of patients. The gene responsible for the Wolfram syndrome on the short arm of the 4p16.1 chromosome has been identified [12]. The pathogenesis of the disease is still not well known, particularly concerning the causes of the onset of juvenile diabetes mellitus and the other main neurodegenerative anomalies which characterise the clinical feature. Nevertheless, some authors [13,14]
Wolfram syndrome believe that, among the ethiologic factors, a mitochondrial alteration, as for some dysmorphogenetic anomalies (optic atrophy, deafness, diabetes mellitus etc.) of Wolfram syndrome, cannot be excluded. As far as the diagnostic problem of the disease is concerned, there are not actually semeiological clinical data that are able to give a easy solution. The only valid elements for the early diagnosis are the diabetes mellitus and the optic atrophy. The first one appears in a range between 3 weeks and 16 years (mean age of 6 years); it is sensitive to insulinic therapy and it does not seem to give vascular complications. Some authors [15] believe in the possibility that the cause of the Wolfram syndrome may be the same as that of diabetes mellitus. The optic atrophy appears in a period ranging between 6 weeks and 9 years (mean age of 14 years). It is a degenerative damage of the optic nerve and provokes a progressive visual deficit. Another alteration that occurs later (between 3 and 40 years, mean age of 14 years) is diabetes insipidus, even if it may be absent. Histopathological and clinical studies demonstrated that this complication is due to atrophy and gliosis of all the supraoptic and paraventricular neurohypophysaroious system [16—18]. The hearing loss is present in 60% of cases and occurs in a period ranging between 5 and 39 years (mean age of 16 years). The audiometric feature (Fig. 1) is characterised by a severe auditory threshold shift which is more evident for the medium-high frequencies. It is a sensorineural hearing loss with an increased latency of the V wave at the auditory evoked potentials. According to some authors [19,20] it seems to be not only a disfunction of the cochlear neurons and of the VIII nerve fibres but also of the central nervous ways at the level of brain stem and inferior colliculus. Describing the otoneurological clinical feature of our case, the presence of both, a horizontal jerky towards the left nystagmus and vertical upbeat nystagmus is pointed out (Fig. 2). This is probably a vestibular nystagmus of central origin not due to ocularmotor anomalies. As is well known, this nystagmus is a sign of damage to the central nervous structures in the bulbar or cerebellar region or damage to the cerebellar—bulbar or cerebellar—pontine connections. In literature [3,19] the presence of nystagmus is described in some patients with Wolfram syndrome without a semeiological definition. Also the origin of the so-called neurological vesica, an anomaly which is observed in 2/3 of the patients has to be linked to an analogous neurodegenerative damage. The urinary disturbances already appear by the age of 10 but they may appear later, by the age of 35 (mean age of 20 years).
245 They are characterised by urinary frequency, incontinence. The urodynamic damage is frequently by idroureteronephrosis with renal insufficiency and recurrent infections [21—24]. In the period ranging between 5 and 44 years (mean age of 30 years) some neurological disturbances such as ataxia, postural defects mioclonus, dysartria, crises of apnea of central origin, hypogeusia, anosmia, hemiparesis, etc. may also occur. It is, generally, a diffusion of the degenerative process which affects at first some nervous regions: optical nerve, posterior lobus of hypophysis, hearing ways, provoking visual deficit, diabetes insipidus, hearing loss and subsequently it spreads affecting also other structures (the brain stem, the cerebellum and the cerebral cortex) as demonstrated by MR study [25]. The results of the autoptic examinations [26] also confirm the presence of a degenerative process of the central nervous structures. This is characterised by a reduction in the numbers of neurons and axons and is often associated with a gliosis and widespread area of demielinisation without signs of inflammation [27]. In 25% of cases psychological disturbances may be associated, such as psychosis, variation of the mood and above all depressive crises, etc. The opinions of the authors on the origin of these symptoms are very different. According to some [28] they seem not to depend on the same neurodegenerative process responsible for the neurological complications. These deviations of the affective sphere (above all the depressive crises) may depend [29] on the same causes responsible for the onset of the genetic alteration of the chromosome 4p16. As Fig. 3 shows, in our patient most of the anomalies which characterise the Wolfram syndrome appear in the course of the years. In relation to the statistical mean age of onset of the different signs, in our case diabetes mellitus, renal alterations and deafness appeared in earlier age, while renal alteration appeared later. The presence of neurologic abnormalities and diabetes insipidus have not been observed till now, datum that can be explained by the absence of suffering of the central nervous structures. The diagnosis of Wolfram syndrome is not always easy in the first stages of the disease. The suspect may come from the presence of a juvenile diabetes mellitus associated with an optic atrophy, but the presence of these anomalies is not certainly sufficient. In fact, there are other clinical features which are characterised by these disturbances such as the ataxic syndrome of Friedriech, the syndrome of Refsum, of Kearn—Savre, of Alstrom, of Lewrence—Moon, the hereditary optic atrophy of Leber, the hereditary deafness associated
246
D. Megighian, M. Savastano
statistical mean age of onset diabetes mellitus
age of onset in the case report optic atrophy
renal abnormalities
deafness
ataxia
neurologc abnormalities
0
Fig. 3
5
10
15
20
25
30
35
Age of onset of the different disturbances in the case report vs. the statistical mean age of onset.
with diabetes mellitus caused by ‘‘3243’’ mitochondrial mutation of the DNA, etc. For the diagnosis a valid clue can be given from the results of some clinical tests such as the positivity of the visual evoked potentials and electroretinogram reliefs and the exclusion of the autoimmune origin of the diabetes mellitus. The subsequent onset of a progressive sensorineural hearing loss, of a nystagmus, which is a sign of the initial sufference of the vestibular nervous districts at bulbar and/or cerebellar level, of urodynamic disturbances and renal complications due to the presence of a neurologic vesica, makes the diagnosis of this syndrome easier. According to Kinsley et al. [30], the recognition of these clinical differences from classic type I diabetes is very important because from that depends its correct therapy. The earlier the treatment the more favourable the results ‘‘quoad vitam’’, considering that the mortality index of the patients with Wolfram syndrome is about 65% before 35 years of age.
References [1] D. Wolfram, H.P. Wagener, Diabetes mellitus and simple optic atrophy among siblings: report of four cases, Proc. Staff Meet. Mayo Clin. 13 (1938) 715—718.
[2] A. Okten, Y. Gedik, A. Demirci, H. Mocan, E. Erduran, Y. Aslan, Various clinical aspects of DIDMOAD (Wolfram) syndrome, Turk. J. Pediatr. 37 (1995) 235—240. [3] T.G. Barrett, S.E. Bundey, Wolfram (DIDMOAD) syndrome, J. Med. Genet. 34 (1997) 838—841. [4] A. Hernandez-Mijares, C. Morillas, A. Lluch, M.L. Martinez-Triguero, M. Munoz, M. Gomez, M.A. Merino, M.A. Escudero, Partial Wolfram syndrome (DIDMOAD): two new patients in a family. Diabetes insipidus, diabetes mellitus optic atrophy and deafness, Diabetes Care 22 (1999) 1378—1379. [5] M. Fukui, Y. Kitagawa, N. Nakamura, T. Yoshikawa, Adult-onset type 1 diabetes with DIDMOAD syndrome-like manifestations, Arch. Intern. Med. 161 (2001) 767—768. [6] Y. Yokoyama, Diabetes (insipidus/mellitus)–—optic atrophydeafness, Ryokibetsu Shokogun Shirizu 33 (2001) 553—554. [7] G. Imataka, H. Yamanouchi, Wolfram syndrome, Nippon Rinsho 60 (Suppl 4) (2002) 466—468. [8] N.J. Scolding, H.F. Kellar-Wood, C. Shaw, J.M. Shneerson, N. Antoun, Wolfram syndrome: hereditary diabetes mellitus with brainstem and optic atrophy, Ann. Neurol. 39 (1996) 352—360. [9] S. Hofmann, R. Bezold, M. Jaksch, P. Kaufhold, B. Obermaier-Kusser, K.D. Gerbitz, Analysis of the mitochondrial DNA from patients with Wolfram (DIDMOAD) syndrome, Mol. Cell Biochem. 174 (1997) 209—213. [10] T.M. Strom, K. Hortnagel, S. Hofmann, F. Gekeler, C. Scharfe, W. Rabl, K.D. Gerbitz, T. Meitinger, Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) for a predicted transmembrane protein, Hum. Mol. Genet. 7 (1988) 2021—2028. [11] T.G. Barrett, S.E. Bundey, A.F. Macleod, Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome, Lancet 346 (1995) 1458—1463.
Wolfram syndrome [12] M.H. Polymeropoulos, M. Swift, Linkage of the gene for Wolfram syndrome to markers on the short arm of chromosome 4, Nat. Genet. 8 (1994) 95—97. [13] S. Bundey, K. Poulton, H. Withwell, E. Curtis, I.A.R. Brown, A.R. Fielder, Mitochondrial abnormalities in the DIDMOAD syndrome, J. Inherit. Metab. Dis. 15 (1992) 315—319. [14] A. Barrientos, J. Casademont, A. Saiz, Autosomal recessive Wolfram syndrome associated with an 8.5-kb mtDNA single deletion, Am. J. Hum. Genet. 58 (1996) 963—970. [15] T. Awata, K. Inoue, S. Kurihara, T. Ohkubo, I. Inoue, T. Abe, H. Takino, Y. Kanazawa, S. Katayama, Missense variations of the gene responsible for Wolfram syndrome (WFS1/wolframin) in Japanese: possible contribution of the Arg 456His mutation to type 1 diabetes–—as a nonautoimmune genetic basis, Biochem. Biophys. Res. Commun. 268 (2000) 612—616. [16] U.M. Mayer, H.D. Rott, H.J. Böhles, Observation concerning the age of onset and the nature of optic atrophy in Wolfram’s syndrome (DIDMOAD), Ophtalmic. Paediatr. Genet. 3 (1985) 155—157. [17] T.G. Barrett, S.E. Bundey, A.R. Fielder, P.A. Good, Optic atrophy in Wolfram (DIDMOAD) syndrome, Eye 11 (1997) 882—888. [18] M. Al-Till, N.S. Jarrah, K.M. Ajlouni, Ophtalmologic findings in fifteen patients with Wolfram syndrome, Eur. J. Ophtalmol. 12 (2002) 84—88. [19] D. Genis, A. Davalos, A. Molins, I. Ferrer, Wolfram syndrome: a neuropathological study, Acta Neuropathol. (Berlin) 93 (1997) 426—429. [20] H. Hattori, H. Inada, K. Tanaka, S. Niihira, T. Seto, O. Matsouka, G. Isshiki, Auditory brainstem responses (ABR) in patients with Wolfram syndrome, No To Hattatsu 30 (1998) 387—393.
247 [21] G.J. Monllor, F. Tano Pino, P. Rodriguez Arteaga, P.F. Galbis, Urologic manifestations in Wolfram syndrome, Acta Urol. Esp. 20 (1996) 474—477. [22] A. Sumboonnanonda, A. Vongiirad, V. Suntompoch, K. Angsusingha, P. Perichatikanond, T. Laohapand, Renal failure in two patients with Wolfram syndrome, J. Pediatr. Endocrinol. Metab. 10 (1997) 645—651. [23] S. Tekgul, O. Oge, E. Simsek, N. Yordan, S. Kendi, Urological manifestations of the Wolfram syndrome: observation in 14 patients, J. Urol. 161 (1999) 616—617. [24] F.J. Anglada Curada, M. Leva Vallejo, A. Blanco Espinosa, R. Prieto Castro, J.C. Regueiro Lopez, P. Moreno Arcas, M.J. Requena Tapia, Wolfram syndrome. Urologic implications, Acta Urol. Esp. 24 (2000) 504—508. [25] P. Galluzzi, G. Filosomi, I.M. Vallone, A.M. Bardelli, C. Venturi, MRI of Wolfram syndrome (DIDMOAD), Neuroradiology 41 (1999) 729—731. [26] P. Shannon, L. Becker, J. Deck, Evidence of widespread axonal pathology in Wolfram syndrome, Acta Neuropathol. (Berlin) 98 (1999) 304—308. [27] J.B. Gregorios, Wolfram’s syndrome with schizophrenia and central hypoventilation: a neuropathological study, J. Neuropathol. Exp. Neurol. 48 (1989) 308—310. [28] M. Swift, R.G. Swift, Psychiatric disorders and mutations at the Wolfram syndrome locus, Biol. Psychiatry 47 (2000) 787—793. [29] K.L. Evans, D. Lawson, T. Meitinger, D.H. Blackwood, D.J. Porteous, Mutational analysis of the Wo9lfram syndrome gene in two families with chromosome 4p-linked bipolar affective disorder, Am. J. Med. Genet. 96 (2000) 158—160. [30] B.T. Kinsley, M. Swift, R.H. Dumont, R.G. Swift, Morbidity and mortality in the Wolfram syndrome, Diabetes Care 18 (1995) 1566—1570.
CASE REPORT
Wolfram syndrome David Megighian, Marina Savastano* Dipartimento di Specialità Medico-Chirurgiche, Sezione ORL, Padua University, Via Giustiniani 2, 35128 Padua, Italy Received 1 June 2003 ; received in revised form 30 September 2003; accepted 8 October 2003
KEYWORDS Wolfram syndrome; Main and associated anomalies; Diagnosis
Summary The Wolfram syndrome is a rare dysmorphogenetic disease of autosomic recessive hereditary nature. The pathogenesis of the disease is still not well known. It is characterised by the presence of diabetes insipidus, diabetes mellitus, optic atrophy and deafness. Other anomalies, such as renal outflow tracts and multiple neurological disorders may develop later. In our case report the diabetes mellitus appeared at the age of 4; the hearing loss and renal disturbances at the age of 11; the optic atrophy at the age of 16. No signs of ataxia, diabetes insipidus and neurologic anomalies were found. The diagnosis of Wolfram syndrome is not always easy in the first stages of the disease. The suspect may come from the presence of a juvenile diabetes mellitus asssociated with optic atrophy. For the diagnosis a valid clue can be given from the results of some clinical tests such as the positivity of the visual evoked potentials and the retinogram reliefs and the exclusion of the autoimmune origin of the diabetes mellitus. Other signs such as the progressive sensorineural hearing loss, the presence of nystagmus and of urodynamic disturbances and renal complications makes the diagnosis of this syndrome easier. © 2003 Elsevier Ireland Ltd. All rights reserved.
1. Introduction In 1938 Wolfram for the first time observed, and then with Wagener described, a clinical feature characterised by diabetes mellitus, optic atrophy and deafness [1]. These anomalies appeared in four brothers in different periods during the first and second decades of life. An atypical form of ataxia occurred in one of these patients and there was a neurological vesica in another later. In the following years, other anomalies, diabetes insipidus, neuropsychical and endocrinal disturbances, were added, thus increasing the original symptomatological feature. For this reason the same Wolfram syn∗ Corresponding author. E-mail address: [email protected] (M. Savastano).
drome is defined with the term Wolfram DIDMOAD syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, deafness) in literature [2—7]. It is a recessive hereditary disease; its pathogenesis is still little known [8—10].
2. Case report D.N.C., 13-year-old, hospitalised by the Urological department because affected by hydronephrosis, due to a suspected neurological vesica and the outcome of bilateral nephrostomia. He is the son of consanguineous (first cousins) parents, who are healthy as is the older sister. On the basis of the anamnesis there is no hereditary disease in the ascendants. From the age of 4, because of the onset of diabetes mellitus, the patient undergoes insulinic
0165-5876/$ — see front matter © 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijporl.2003.10.012
244
dB 0 10 20 30 40 50 60 70 80 90 100 110 120
250 500 1000 2000 4000 8000 10000
Fig. 1 years.
Nº of jerky eye movements
therapy. The glycemia has been well compensated till now. There is no diabetes insipidus present, a complication which in some cases may occur also later, caused by a degenerative alteration of the nervous cerebral structures at the level of the supraoptic and paraventricular districts. During hospitalisation the patient underwent various tests. A urovideodynamic test reveals, besides bilateral hydronephrosis, a pluridiverticolar vesica with hyperreflexic waves of twitch. A renal angiophotoscintigraphy with closed nephrostomy, indicates a functionality of 81% in the left kidney and of 19%. in the right kidney. There are no signs of neurologic disturbances but from the neuropsychiatric point of view there is a risk of depression because of obsessive attention to his physical problems. An internal check-up reveals too much weight because of reduced physical activity. The oculistic examination does not reveal any sign of diabetic retinopathy. The papillae are pale-rosy and the peripheric vessels and the maculae are regular. The pupillar reflexes are very slow. The visual deficit is progressively worsening. At the age of 14 the visus is still 2/10 bilaterally but an exotropya appears on the left eye. After 1 year his visus is reduced to 1/10 only in the right eye. At the age of 16 in the right eye it is only possible to count fingers from 2 m; in the left eye the visus is reduced to 1/10. The first sign of optic atrophy appears. After another year the finger count was reduced to 1 m in the right eye, while the visus remains 1/10 in the left eye. The signs of optic atrophy are more evident. At the age of 18 the finger count is reduced to 50 cm, the visus remains 1/10 in the left one. The electroretinogram is normal and there is absence of retina—cortical conduction at the evoked visual potentials. The visus is today unchanged. The ENT examination is normal while the liminar audiometry demonstrates a bilateral symmetric sensorineural hearing loss prevalent for the medium-high frequencies. Considering the entity of the hearing handicap, two hearing aids were applied (Fig. 1). The auditory brain stem responses (ABR) indicate a little increase in the V wave latency at 80 dB of stimulus intensity. From a vestibular point of view, two types of nystagmus are present: one is a horizontal jerky nystagmus towards the left with a rotary component and the other one is an upbeat vertical nystagmus. As far as the opticcynetic stimulation is concerned, the opticcynetic horizontal nystagmus (NOC) is bilaterally altered while the evoked vertical NOC appears normal. The caloric stimulation by Veits (20◦ ) is normal (Fig. 2).
D. Megighian, M. Savastano
Hz
Liminar audiometry feature at the age of 13
100 90 80 70 60 50 40 30 20 10
right ear left ear stimulation stimulation
horizontal nystagmus
upbeat vertical nystagmus
Fig. 2 Numbers of jerky eye movements, at the caloric stimulation by Veits (20◦ ) and numbers of jerky eye movements of horizontal and vertical nystagmus.
The psychological condition has worsened because the patient is not able to accept the deficit of the visual and auditory functions.
3. Considerations The Wolfram syndrome is a rare dysmorphogenetic disease, which affects 1 every 500,000 young people. According to Barrett et al. [11] this incidence seems to be greater in consanguineous parents (as in the case described by us), but the possibility that the same clinical form may appear also in relatives of eterozygotous subjects cannot be excluded. The autosomic recessive hereditary nature of the disease has been confirmed by studies made on a large number of patients. The gene responsible for the Wolfram syndrome on the short arm of the 4p16.1 chromosome has been identified [12]. The pathogenesis of the disease is still not well known, particularly concerning the causes of the onset of juvenile diabetes mellitus and the other main neurodegenerative anomalies which characterise the clinical feature. Nevertheless, some authors [13,14]
Wolfram syndrome believe that, among the ethiologic factors, a mitochondrial alteration, as for some dysmorphogenetic anomalies (optic atrophy, deafness, diabetes mellitus etc.) of Wolfram syndrome, cannot be excluded. As far as the diagnostic problem of the disease is concerned, there are not actually semeiological clinical data that are able to give a easy solution. The only valid elements for the early diagnosis are the diabetes mellitus and the optic atrophy. The first one appears in a range between 3 weeks and 16 years (mean age of 6 years); it is sensitive to insulinic therapy and it does not seem to give vascular complications. Some authors [15] believe in the possibility that the cause of the Wolfram syndrome may be the same as that of diabetes mellitus. The optic atrophy appears in a period ranging between 6 weeks and 9 years (mean age of 14 years). It is a degenerative damage of the optic nerve and provokes a progressive visual deficit. Another alteration that occurs later (between 3 and 40 years, mean age of 14 years) is diabetes insipidus, even if it may be absent. Histopathological and clinical studies demonstrated that this complication is due to atrophy and gliosis of all the supraoptic and paraventricular neurohypophysaroious system [16—18]. The hearing loss is present in 60% of cases and occurs in a period ranging between 5 and 39 years (mean age of 16 years). The audiometric feature (Fig. 1) is characterised by a severe auditory threshold shift which is more evident for the medium-high frequencies. It is a sensorineural hearing loss with an increased latency of the V wave at the auditory evoked potentials. According to some authors [19,20] it seems to be not only a disfunction of the cochlear neurons and of the VIII nerve fibres but also of the central nervous ways at the level of brain stem and inferior colliculus. Describing the otoneurological clinical feature of our case, the presence of both, a horizontal jerky towards the left nystagmus and vertical upbeat nystagmus is pointed out (Fig. 2). This is probably a vestibular nystagmus of central origin not due to ocularmotor anomalies. As is well known, this nystagmus is a sign of damage to the central nervous structures in the bulbar or cerebellar region or damage to the cerebellar—bulbar or cerebellar—pontine connections. In literature [3,19] the presence of nystagmus is described in some patients with Wolfram syndrome without a semeiological definition. Also the origin of the so-called neurological vesica, an anomaly which is observed in 2/3 of the patients has to be linked to an analogous neurodegenerative damage. The urinary disturbances already appear by the age of 10 but they may appear later, by the age of 35 (mean age of 20 years).
245 They are characterised by urinary frequency, incontinence. The urodynamic damage is frequently by idroureteronephrosis with renal insufficiency and recurrent infections [21—24]. In the period ranging between 5 and 44 years (mean age of 30 years) some neurological disturbances such as ataxia, postural defects mioclonus, dysartria, crises of apnea of central origin, hypogeusia, anosmia, hemiparesis, etc. may also occur. It is, generally, a diffusion of the degenerative process which affects at first some nervous regions: optical nerve, posterior lobus of hypophysis, hearing ways, provoking visual deficit, diabetes insipidus, hearing loss and subsequently it spreads affecting also other structures (the brain stem, the cerebellum and the cerebral cortex) as demonstrated by MR study [25]. The results of the autoptic examinations [26] also confirm the presence of a degenerative process of the central nervous structures. This is characterised by a reduction in the numbers of neurons and axons and is often associated with a gliosis and widespread area of demielinisation without signs of inflammation [27]. In 25% of cases psychological disturbances may be associated, such as psychosis, variation of the mood and above all depressive crises, etc. The opinions of the authors on the origin of these symptoms are very different. According to some [28] they seem not to depend on the same neurodegenerative process responsible for the neurological complications. These deviations of the affective sphere (above all the depressive crises) may depend [29] on the same causes responsible for the onset of the genetic alteration of the chromosome 4p16. As Fig. 3 shows, in our patient most of the anomalies which characterise the Wolfram syndrome appear in the course of the years. In relation to the statistical mean age of onset of the different signs, in our case diabetes mellitus, renal alterations and deafness appeared in earlier age, while renal alteration appeared later. The presence of neurologic abnormalities and diabetes insipidus have not been observed till now, datum that can be explained by the absence of suffering of the central nervous structures. The diagnosis of Wolfram syndrome is not always easy in the first stages of the disease. The suspect may come from the presence of a juvenile diabetes mellitus associated with an optic atrophy, but the presence of these anomalies is not certainly sufficient. In fact, there are other clinical features which are characterised by these disturbances such as the ataxic syndrome of Friedriech, the syndrome of Refsum, of Kearn—Savre, of Alstrom, of Lewrence—Moon, the hereditary optic atrophy of Leber, the hereditary deafness associated
246
D. Megighian, M. Savastano
statistical mean age of onset diabetes mellitus
age of onset in the case report optic atrophy
renal abnormalities
deafness
ataxia
neurologc abnormalities
0
Fig. 3
5
10
15
20
25
30
35
Age of onset of the different disturbances in the case report vs. the statistical mean age of onset.
with diabetes mellitus caused by ‘‘3243’’ mitochondrial mutation of the DNA, etc. For the diagnosis a valid clue can be given from the results of some clinical tests such as the positivity of the visual evoked potentials and electroretinogram reliefs and the exclusion of the autoimmune origin of the diabetes mellitus. The subsequent onset of a progressive sensorineural hearing loss, of a nystagmus, which is a sign of the initial sufference of the vestibular nervous districts at bulbar and/or cerebellar level, of urodynamic disturbances and renal complications due to the presence of a neurologic vesica, makes the diagnosis of this syndrome easier. According to Kinsley et al. [30], the recognition of these clinical differences from classic type I diabetes is very important because from that depends its correct therapy. The earlier the treatment the more favourable the results ‘‘quoad vitam’’, considering that the mortality index of the patients with Wolfram syndrome is about 65% before 35 years of age.
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