Most WS1 patients (>60%) have been shown to exhibit neurological symptoms at a mean age of 40 years (range 5–44 years)
[5], but in some cases, onset is earlier
[9][28][10,71]. De Heredia et al. found the onset of neurological complications at the mean age of 23 years, with two peaks of greater frequency, one at 13 years and the other at 30 years
[7][23]. Cerebellar ataxia of the trunk is the most common manifestation (45%), and a neurological counseling one or two times a year is recommended
[11][55]. Other neurological abnormalities are peripheral neuropathy (39%), cognitive impairment (32%), epilepsy (26%), and lastly, dysarthria, dysphagia, and nystagmus (10%)
[11][55]. Severe complications, such as aspiration pneumonia, can be prevented by swallowing therapy. Esophageal dilatation and esophagomyotomy are useful in some cases. Neurological symptoms, such as loss of the gag reflex, decreased ability to taste and smell, orthostatic hypotension, anhidrosis, hypohidrosis or hyperhidrosis, constipation, gastroparesis, hypothermia, or hyperpyrexia, may often be reported
[11][55]. Atrophy of the brain, cerebellum, and brainstem are abnormalities found by nuclear magnetic resonance imaging (MRI) in 54% of WS1 patients
[11][55]. Respiratory failure or dysphagia are common causes of mortality
[5][11][5,55]. Thus far, the progression of neurological manifestations cannot be slowed down, as there is no therapy. Psychiatric disorders, such as severe depression with suicide attempts, psychosis, sleep abnormalities, verbal impulsivity, and physical aggression, can complicate the clinical picture in WS1 patients. Moreover, a predisposition to psychiatric diseases was found in
WFS1 heterozygotes
[29][72]. Cognitive performance is generally normal. However, Chaussenot et al. found that 32% of 59 studied WS1 patients had cognitive impairment
[11][55]. It has been suggested that the smell and sleep alterations can be used as indicators to follow-up WS1 patients with psychiatric manifestations
[30][73].
8. Urological Abnormalities
Neurogenic bladder, which causes hydroureteronephrosis, urinary incontinence, and recurrent infections, has frequently been found in WS1 patients
[11][55]. Urinary tract abnormalities have been found in up to 90% of patients. The average age of onset is 20 years old, and specifically, three high-frequency peaks were found: one at 13 years, the second at 21, and the third at 33 years
[7][23].
Neurogenic bladder and upper urinary tract dilation are the main urological abnormalities. Anticholinergic drugs and clean intermittent catheterization are therapeutic tools for neurogenic bladder
[7][23]. Some WS1 patients also undergo electrical stimulation and physiotherapy
[2]. Follow-up is carried out through clinical, instrumental, and laboratory checks of renal function. Moreover, the measurement of the residual urinary volume after voiding by ultrasound and urodynamic tests are needed. Urinary tract infections at a very early age are the first manifestations of WS1 only in rare cases
[31][74]. Urine culture is required in WS1 patients suffering from fever or other symptoms, such as headache. Yuca et al. described a Turkish family in which the course of chronic renal failure was rapidly progressive in some WS1-affected members
[32][75].
9. Endocrinology and Reproductive Biology
Primary and secondary hypogonadism, more frequent in males, are the main manifestations of endocrine function impairment in WS1 patients. Delayed menarche and menstrual cycle alterations are frequent in WS1 females, but ovarian function is normal, and some pregnant patients have been described
[15][59]. Short stature, growth hormone (GH) deficiency, and impaired corticotrophin secretion were found in WS1 patients
[5] due to anterior pituitary hypofunction of hypothalamic origin
[15][59]. Growth rate and pubertal development must be closely monitored for GH therapy, and steroid supplementation should be considered during stressful periods, such as severe infections
[33][76].
10. Additional Anomalies
Gastrointestinal disorders include gastroparesis (29%), bowel dysmotility (24%), and bowel incontinence
[28][71]. Congenital heart diseases, such as Fallot’s tetralogy and pulmonary valve stenosis, have been reported in rare cases of WS1
[15][34][35][59,77,78], and hence, heart monitoring is recommended.
11. Diagnosis of WS1
A careful and accurate diagnosis of WS1 allows for early identification of patients so that appropriate interventions can be initiated. History and clinical manifestations, such as the diagnosis of OA after that of DM under the age of 16, should lead to suspicion of WS1. Visual abnormalities and insulin-dependent DM must be carefully evaluated in WS1 patients, as they may be misdiagnosed as T1D with diabetic retinopathy. This mistake would cause a delay in diagnosis of WS1
[2][36][2,13]. Given the clinical complexity of WS1, alterations such as DI, sensorineural D, and neurological and urological symptoms together with non-auto-immune insulin-dependent DM or OA, allow to suspect WS1. Differential diagnosis should be made with mitochondrial diseases, deafness caused by
WFS1 mutations, autosomal dominant OA, Bardet–Biedl syndrome, Alström syndrome, and Friedreich ataxia
[15][59]. Genetic tests, such as exome sequencing and genome sequencing-based diagnostic methods, are valuable tools to confirm or rule out the diagnosis of WS1. Sequencing of the entire
WFS1 with all eight exons and their flanking intronic regions is recommended
[9][37][10,79]. Early diagnosis of WS1 is imperative to enable successful follow-up that includes specialist consultations and appropriate instrumental and laboratory tests. If WS1 is suspected, thorough genetic counseling should be done to study family members even if they are asymptomatic.